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Single Nucleotide Polymorphism in SMAD7 and CHI3L1 and Colorectal Cancer Risk.

1. Colorectal Cancer

Colorectal cancer (CRC) has attracted significant attention as it represents the third most common cancer and fourth cancer in mortality in the world after lung, stomach, and liver cancers [1]. Colorectal cancer accounts for approximately 10% of all new cancer cases, affecting one million people every year throughout the world [2]. The highest incidence rates are mainly found in developed countries, whereas the lowest rates are found in developing countries (Figure 1) [3]. From the genetic standpoint, CRC can be divided into three types: sporadic, familial, and hereditary CRC [4] as shown in Table 1.

The etiology of sporadic CRC is considered to be multifactorial and arises from the interaction between allelic variants in low-penetrant genes and environmental risk factors [5, 6]. Penetrance is the frequency with which the characteristics transmitted by a gene appear in individuals possessing it. A highly penetrant gene almost always expresses its phenotypes regardless of other environmental influence, while low-penetrant genes express its phenotype in the presence of other genetic and/or environmental influence [7]. The genetic contribution of high- and low-penetrant genes to CRC is shown in Figure 2. Risk factors for CRC may be nonmodifiable or modifiable [8] as shown in Table 2.

Vogelstein model, also known as the adenomacarcinoma sequence, is a multistep model [19] that describes the progression of CRC carcinogenesis from a benign adenoma to a malignant carcinoma through a series of well-defined histological stages (Figure 3). The main features of the model include a mutational activation of oncogenes and/or the inactivation of tumor suppressor genes. At least four or five genetic alterations must take place for the formation of malignant tumors. The characteristics of the tumor are dependent upon the accumulation of multiple genetic mutations rather than a certain sequence of mutations of these genes.

Dukes' colorectal cancer staging and Tumors/Nodes/ Metastases (TNM) are the two classification system that are used for the staging of CRC (Table 3). There has been a gradual move from Dukes' to the TNM classification system as TNM was reported to give a more accurate independent description of the primary tumors and its spread [20].

2. Prevention of Colorectal Cancer

Several approaches have been developed to reduce CRC incidence and mortality. Prevention includes primary and secondary strategies. Primary strategy includes dietary changes, increasing physical activity, and the use of nonsteroidal anti-inflammatory drugs (NSAIDs), while the secondary strategy is based on screening tests (Table 4).

Interestingly, dietary factors are responsible for 70% to 90% of CRC. The relatively low CRC rates in the Mediterranean area compared with most Western countries are mostly because the traditional Mediterranean diet is characterized by high consumption of foods of plant origin, relatively low consumption of red meat, and high consumption of olive oil [32]. Therefore, diet modification could potentially help to reduce the incidence of CRC [33, 34]. Examples of some dietary components that lower CRC risk are shown in Table 5.

Early diagnosis of CRC is important to improve outcomes. Fecal occult blood testing (FOBT) or fecal immunochemical test (FIT) is routinely used prior to colonoscopy, and only patients with a positive test result are referred to a specialist. Although these assays are useful screening tools, patient compliance with these stool-based assays tends to be low. Serum-based assays for the early detection of CRC are highly attractive, as they could be integrated into any regular health checkup without the need for additional stool sampling, thereby increasing acceptance among patients [29].

3. Gene Polymorphism

Polymorphism is the occurrence of two or more clearly different morphs or forms of a species in the population. Poly means many; morph means form [48]. The colored flowers of mustard, butterflies, and human ABO blood group system are obvious examples of polymorphisms [49, 50].

Genetic polymorphisms are different forms of the DNA sequence, which may or may not affect biological function depending on its exact nature. Polymorphism arises as a result of mutation. If the frequency of a specific sequence variant reaches 1% or more in the population, it is referred to as polymorphism, and if it is lower than 1%, the allele is typically regarded as mutation [51]. Molecular polymorphism, first demonstrated in Drosophila pseudoobscura, stimulated molecular studies of many other organisms and led to vigorous theoretical debate about the significance of the observed polymorphisms [52, 53].

Single nucleotide polymorphism (SNP) is a variation in a single nucleotide that occurs at a specific position in the genome. Single nucleotide polymorphisms are the most abundant type of genetic variation in the human genome, accounting for more than 90% of all differences between individuals [54]. Single nucleotide maybe changed (substitution), removed (deletion), or added (insertion) to a polynucleotide sequence [54].

Single nucleotide polymorphisms are also thought to be the keys in realizing the concept of personalized medicine as it can affect how humans develop diseases and respond to pathogens, chemicals, drugs, vaccines, and other agents. Single nucleotide polymorphisms underlie the differences in the susceptibility to a wide range of human diseases, for example, a single base mutation in the apolipoprotein E gene is associated with a higher risk for Alzheimer's disease. The severity of illness and the way the body responds to treatments are also manifestations of genetic variations [55, 56].

According to their location in the genome, SNPs are classified into cSNP in the coding region (exons), rSNP in the regulatory region, and iSNP located in the intronic region [54].

Polymorphisms in the coding region are either synonymous or nonsynonymous (Figure 4). Synonymous polymorphisms do not result in a change of amino acid in the protein but still can affect its function in other ways. Silent mutation in the multidrug resistance gene 1, which codes for a cellular membrane pump that expels drugs from the cell, is an example of synonymous polymorphism. It can slow down translation and allow unusual folding of the peptide chain, causing the mutant pump to be less functional [57, 58].

Nonsynonymous polymorphisms, on the other hand, can change the amino acid sequence of the protein and subclassified into missense and nonsense. Missense polymorphism results in different amino acids such as single base change G > T in LMNA gene that results in the replacement of the arginine by the leucine at the protein level, which manifests progeria syndrome [59]. Nonsense polymorphism results in a premature stop codon and usually nonfunctional protein product such as that manifested in cystic fibrosis caused by mutation in the cystic fibrosis transmembrane conductance regulator gene [60].

Promoter polymorphism can cause variations in gene expression as it affects the DNA binding site and alters the affinity of the regulatory protein while intronic region polymorphism may affect gene splicing and messenger RNA degradation [61, 62].

Genotyping technologies typically involve the generation of allele-specific products for SNPs of interest followed by their detection for genotype determination. All current genotyping technologies with only a few exceptions require the polymerase chain reaction (PCR) amplification step. In most technologies, PCR amplification of a desired SNP-containing region is performed initially to introduce specificity and increase the number of molecules for detection following allelic discrimination [63]. Enzymatic cleavage, primer extension, hybridization, and ligation are four popular methods used for allelic discrimination (Table 6).

4. Genome-Wide Association Study and Colorectal Cancer

Genome-wide association study (GWAS), also known as whole genome association study, is defined as an examination of many common SNPs in different individuals to see if any SNP is associated with a disease. Genome-wide association study compares the DNA of participants having a disease with similar people without the disease. The ultimate goal is to determine genetic risk factors that can be used to make predictions about who is at risk for a disease and to identify their role in disease development for developing new prevention and treatment strategies [68].

The availability of chip-based microarray technology that assay hundreds and thousands of SNPs made genomewide association studies easy to be performed (Table 7). Genome-wide association study identifies a specific location, not complete genes. Many SNPs identified in GWAS are near a protein-coding gene or are within genes that were not previously believed to associate with the disease. So, researchers use data from this type of study to pinpoint genes that may contribute to a person's risk of developing a certain disease [69].

Genome-wide association study is built on the expanding knowledge of the relationships among SNPs generated by the international HapMap project. The HapMap project is an international scientific effort to identify common SNPs among people from different ethnic populations. When several SNPs cluster together on a chromosome, they are inherited as a block known as a haplotype. The HapMap describes haplotypes, including their locations in the genome, and how common they are present in different populations throughout the world [70].

Genome-wide association study is an important tool for discovering genetic variants influencing a disease, but it has important limitations, including their potential for false-positive and false-negative results and for biases related to selection of study participants and genotyping errors [71]. The gold standard for validation of any GWAS is replication in an additional independent sample. Replication studies are performed in an independent set of data drawn from the same population as the GWAS, in an attempt to confirm the effect in the GWAS target population. Once an effect is confirmed in the target population, other populations may be sampled to determine if the SNP has an ethnic-specific effect [72].

It has been recognized that SNPs play an important role in conferring risk of CRC. Genome-wide association studies have reported multiple risk loci associated with risk CRC, some of which are involved in the transforming growth factor-[beta] (TGF-[beta]) signaling pathway [73]. For example, SMAD7 rs4939827 was found to be associated with CRC in two GWASs [74, 75]. The association of SMAD7 rs4939827 with CRC was confirmed by other replication studies [76, 77]. A summary of other SNPs studied as risk factors for CRC is shown in Table 8.

5. Transforming Growth Factor-[beta] Signaling and Its Regulatory Smad7

Mothers against decapentaplegic homolog 7 (Smad7) is a key inhibitor of TGF-[beta] [94, 95]. Smad7 was named after mothers against decapentaplegic (mad), an intermediate of the decapentaplegic signaling pathway in Drosophila melanogaster and sma-gene in Caenorhabditis elegans that has mutant phenotype similar to that observed for the TGF-[beta]like receptor gene [96]. Regulation of TGF-[beta] by Smad7 is crucial to maintain gastrointestinal homeostasis [97]. Smad7 overexpression is commonly found in patients with chronic inflammatory conditions of the colon [98] and may be associated with prognosis in patients with CRC [99]. Loss of Smad/TGF-[beta] signaling interrupts the principal role of TGF-[beta] as a growth inhibitor, allowing unchecked cellular proliferation [100].

In the early 1980s, Roberts and his colleagues isolated two fractions that could induce growth of normal fibroblasts from murine sarcoma cell extracts and were named TGF[alpha] and TGF-[beta] [101, 102]. Transforming growth factor-[beta] is a prototype of a large family of cytokines that includes the TGF-[beta]s, activins, inhibins, and bone morphogenetic proteins (BMPs) [103].

In mammals, TGF-[beta] has 3 isoforms (TGF-[beta]1, TGF[beta]-[beta]2, and TGF-[beta]3), with similar biological properties. The TGF-[beta] isoforms are encoded from genes located on different chromosomes. The TGF-[beta]1 gene is located in chromosome 19q13.1, while TGF-[beta]2 and TGF-[beta]3 genes are located in chromosomes 1q4.1 and 14q24.3, respectively [104].

The isoforms of TGF-[beta]1, TGF-[beta]2, and TGF-[beta]3 are encoded as large precursor, which undergo proteolytic digestion by the endopeptidase furin, yielding two products that assemble into dimers. One is latency-associated peptide (LAP), a dimer from the N-terminal region. The other is mature TGF-[beta], a dimer from the C-terminal portion. A common feature of TGF-[beta] is that its N-terminal portion (LAP) remains noncovalently associated with the mature TGF-[beta] forming a small latent complex [105, 106]. The small latent complex is associated with a large protein termed latent TGF-[beta] binding protein (LTBP) via disulfide bonds forming large latent complex for targeted export to the extracellular matrix (ECM) [107, 108]. For TGF-[beta] to bind its receptors, the latent complex must be removed so that the receptor-binding site in TGF-[beta] is not masked by LAP. Latent TGF-[beta] is cleaved by several factors, including proteases, thrombospondin, reactive oxygen species (ROS), and integrins (Figure 5) [109, 110].

Transforming growth factor-[beta] is a pleiotropic cytokine that has a dual function in cancer development, where it acts as a tumor suppressor in the early stages and a tumor promoter in the late stages [111]. The main actions of TGF-[beta] are summarized in Table 9.

The active TGF-[beta] binds to transforming growth factor-[beta] receptor 2 (TGF-[beta]R2), a serine/threonine kinase receptor, leading to the recruitment and phosphorylation of the TGF-[beta]R1 (Figure 6). The activated TGF-[beta]R1 interacts with and phosphorylates a number of proteins, thereby activating multiple downstream signaling pathways in either a Smad-dependent (canonical) or Smad-independent (noncanonical) signaling pathway (Figure 6) [96].

In the canonical pathway, TGF-[beta]R1 propagates the signal through a family of intracellular signal mediators known as Smads. To date, eight mammalian Smad proteins have been characterized and are grouped into three functional classes: receptor-activated Smads (R-Smads) including Smad1, Smad2, Smad3, Smad5, and Smad8, common mediator Smad (Smad4), and inhibitory Smads (I-Smads) including Smad6 and Smad7. Receptor-activated Smads are retained in the cytoplasm by binding to SARA (Smad anchor for receptor activation). Receptor-activated Smads are released from SARA when they are phosphorylated by the activated TGF-[beta]R1 [130, 131].

Once R-Smads (Smad2/3) are activated through phosphorylation by TGF-[beta]R1, they form an oligomeric complex with Smad4 and translocate into the nucleus, where it modulates the transcription of specific genes. Ability of Smads to target a particular gene and the decision to activate or repress gene transcription are determined by many cofactors that affect the Smad complex [130].

In the noncanonical pathway, TGF-[beta] activates other non-Smad signaling pathways (Table 10). Some of these pathways can regulate Smad activation, but others might induce responses unrelated to Smad [132].

Transforming growth factor-[beta] is strongly implicated in cancer as genetic alterations of some common components of TGF-[beta] pathway (Table 11) that have been identified in human tumors [141].

6. Inhibitory Smad (I-Smad, Smad7)

Mothers against decapentaplegic homolog 7 (Smad7) belongs to the third type of Smads, the I-Smads that also include Smad6. The structure of the Smads is characterized by two conserved regions known as the amino terminal (Nterminal) Mad homology domain-1 (MH1) and C-terminal Mad homology domain-2 (MH2), which are joined by a short poorly conserved linker region. The MH1 domain is highly conserved among the R-Smads and the Co-Smad, whereas the I-Smads lack a MH1. The MH2 domain is conserved among all of the Smad proteins but I-Smads lack SXSS motif, which is needed for phosphorylation following TGF-[beta]R1 activation (Figure 7). Thus, I-Smads are not phosphorylated upon binding of TGF-[beta] to its receptors. The L3 loop in the MH2 domain of the R-Smads is a specific binding site for the TGF-[beta]R1 [95, 156].

Smad7 antagonizes TGF-[beta] signaling through multiple mechanisms, both in the cytoplasm and the nucleus (Figure 8). Smad7 antagonizes TGF-[beta] in the cytoplasm through the formation of a stable complex with TGF-[beta]R1, leading to inhibition of R-Smad phosphorylation. Smad7 can recruit E3 ubiquitin ligases that induce the degradation of activated TGF-[beta]R1 complexes [156,157]. Also, Smad7forms a heteromeric complex with R-Smads through the MH2 domain and hence interferes with R-Smad (Smad2/3)-Smad4 oligomerization in a competitive manner. Additionally, Smad7 can bind to DNA disrupting the formation of functional Smad-DNA complexes [158, 159].

Inhibitory Smads can mediate the cross talking of TGF-[beta] with other signaling pathways. Various extracellular stimuli such as interferon-[gamma] (IFN-[gamma]) can induce Smad7 expression to exert opposite effects on diverse cellular functions modulated by TGF-[beta] [161]. In addition, Smad7 was found to be a key regulator of Wnt/[beta]-catenin pathway that is responsible for the TGF-[beta]-induced apoptosis and survival in various cell types [162].

There is a controversy regarding the role of Smad7 in tumor development depending on the type of the tumor. High Smad7 expression was reported to be correlated with the clinical prognosis of patients with colorectal, pancreatic, liver, and prostate cancer. In contrast, a protective role of high Smad7 expression was reported in other tumors [163]. Boulay et al. [164] found that CRC patients with deletion of Smad7 had a favorable clinical outcome compared with patients with Smad7 expression. Additionally, Smad7 was found to act as a scaffold protein to facilitate TGF-[beta]-induced activation of p38 and subsequent apoptosis in prostate cancer cells [162].

Even in the same tumor, the function of Smad7 can switch from tumor suppressive to tumor promoting depending on the tumor stage (i.e., early versus advanced). These apparently contradictory functions are in harmony with the opposite roles of TGF-[beta] signaling pathway in the early versus advanced tumor stages and the interaction of Smad7 with a vast array of functionally heterogeneous molecules that may be differently expressed during the carcinogenic process [160].

The overexpression of Smad7 in CRC cell was reported to enhance cell growth and inhibit apoptosis through a mechanism dependent on suppression of TGF-[beta] signaling [100]. In addition, Smad7-deficient CRC cells were reported to enhance the accumulation of CRC cells in S phase of cell cycle and cell death through a pathway independent on TGF-[beta] [165]. Genetic variants in SMAD7 gene have been extensively studied in CRC patients (Table 12).

7. Chitinase 3 Like 1/YKL-40

YKL-40 is a mammalian member of the chitinase protein family. YKL-40 is a 40 kDa heparin- and chitin-binding glycoprotein. The human protein was named YKL-40 based on its three N-terminal amino acids tyrosine (Y), lysine (K), and leucine (L) and its 40kDa molecular mass [178]. This protein has several names, YKL-40 [178], human cartilage glycoprotein-39 (HC-gp39) [179], 38kDa heparin-binding glycoprotein (Gp38k) [180], chondrex [181], and 40kDa mammary gland protein (MGP-40) [182].

In a search of new bone proteins, the glycoprotein YKL40 was identified in 1989 to be secreted in vitro by the human osteosarcoma cell line MG63. The protein was later found to be secreted by differentiated smooth muscle cells, macrophages, human synovial cells, and nonlactating mammary gland [178,181,182]. In 1997, the chitinase 3 like 1 (CHI3L1) gene encoding for YKL-40 was isolated. It is assigned to chromosome 1q31-q32 and consists of 10 exons and spans about 8 kilobases of genomic DNA [178, 183].

Based on amino acid sequence, it was found that YKL40 belongs to the glycosyl hydrolase family 18 that hydrolyses the glycosidic bond between two or more carbohydrates or between a carbohydrate and a noncarbohydrate moiety. Based on sequence similarity, there are more than 100 different families of glycosyl hydrolases [184-186].

Chitin, a polymer of N-acetyl glucosamine, is the second most abundant polysaccharide in nature, following cellulose. It is found in the walls of fungi, the exoskeleton of crabs, shrimp and insects, and the micro filarial sheath of parasitic nematodes [187]. Chitin accumulation is regulated by the balance of chitin synthase-mediated biosynthesis and degradation by chitinases. Although YKL-40 contains highly conserved chitin-binding domains, it functionally lacks chitinase activity due to the mutation of catalytic glutamic acid into leucine [183].

Several types of solid tumors can express YKL-40 such as osteosarcoma [178], CRC [188], thyroid carcinoma [189], breast [190], ovarian [191], lung [192], pancreatic cancer [193], glioblastoma [194-196], and cholangiocarcinoma [197].

There are several synergistic and antagonistic factors that modulate the regulatory functions of YKL-40 (Figure 9) in both normal and pathological conditions [198].

8. CHI3L1/YKL-40 Targets and Actions

Although the biological function of YKL-40 is not fully understood, the pattern of its expression suggests function in remodeling or degradation of ECM. The diverse roles of YKL-40 in cell proliferation, differentiation, survival, inflammation, and tissue remodeling have been suggested [199]. Aberrant expression of YKL-40 is associated with the pathogenesis of an array of human diseases (Figure 10).

Elevated serum YKL-40 levels were reported to be associated with a wide range of inflammatory diseases (Table 13). More than 75% of patients with streptococcus pneumoniae bacteremia had elevated serum levels of YKL-40 compared with age-matched healthy subjects. Treatment of these patients with antibiotics resulted in reaching serum YKL-40 normal level within few days in most patients before the serum C-reactive protein (CRP) reach the normal level [200].

Biologically, YKL-40 was found to activate a wide range of inflammatory responses. An inflammatory stimulus can trigger the secretion of a variety of cytokines that in turn may regulate YKL-40 (Figure 11). Increased YKL-40 was reported to regulate chronic inflammatory responses like asthma, chronic obstructive pulmonary disease (COPD), cardiovascular disease (CVD), and arthritis. Inhibition of YKL-40 by utilizing anti-CHI3L1 antibody may be a useful therapeutic strategy to control/reduce the effect of inflammatory diseases [198].

Over the past three decades, a considerable attention has been focused on the potential role of YKL-40 in the development of a variety of human cancers. Serum levels of YKL-40 (Table 14) were independent of serum carcinoembryonic antigen (CEA) in CRC [188], serum cancer antigen 125 (CA-125) in ovarian cancer [191], serum human epidermal growth factor receptor 2 (HER-2) in metastatic breast cancer [190], serum lactate dehydrogenase (LDH) in small cell lung cancer [192], and serum prostate-specific antigen (PSA) in metastatic prostate cancer [208]. Therefore, it may be of value to include serum YKL-40 as a biomarker for screening of cancer together with a panel of other tumor markers as it can reflect other aspects of tumor growth and metastasis than the routine tumor markers [201].

Macrophages and neutrophils in tumor microenvironment or tumor cells were found to secrete YKL-40 into extracellular space, which can enhance tumor initiation, proliferation, angiogenesis, and metastasis (Figure 12).

The ability of YKL-40 to induce cytokine secretion, proliferation, and migration of target cells suggests the existence of their receptors on the cell surface. However, receptors interacting with YKL-40 are incompletely characterized, and only limited information is available about YKL-40-induced signaling pathways. There are evidences to strengthen a hypothesis that a cross talk between adjacent membrane-anchored receptors plays a key role in transmitting "outside-in" signaling to the cells, leading to a diverse array of intracellular signaling [213, 214].

YKL-40 possesses heparin-binding affinity, which enables it to specifically bind heparan sulfate (HS) fragments [215]. Syndecans are transmembrane molecules with cytoplasmic domains that can interact with a number of regulators [216]. Syndecan-1 is the major source of cell surface HS. There is compelling evidence demonstrating that syndecan1 can act as a matrix coreceptor with adjacent membrane-bound receptors such as integrins to mediate cell adhesion and/or spreading [217]. It was found that YKL-40 could induce the coupling of syndecan-1 and [alpha]v[beta]3 integrin (Figure 13), resulting in phosphorylation of focal adhesion kinase (FAK) and activation of downstream ERK1/2 signaling pathway, which enhance vascular endothelial growth factor (VEGF) expression in tumor cells, angiogenesis, and tumor growth [214]. Additionally, ERK1/2 and JNK signaling pathways were reported to upregulate proinflammatory mediators such as C-chemokine ligand 2 (CCL2), chemokine CX motif ligand 2 (CXCL2), and MMP-9; all of which contribute to tumor growth and metastasis [218].

Another VEGF-independent pathway was reported to mediate angiogenic activity ofYKL-40, as an anti-VEGF neutralizing antibody failed to impede YKL-40-induced migration [219]. Therefore, targeting both YKL-40 and VEGF could be an efficient course of therapy along with radiotherapy for eventual eradication of deadly diseases.

Furthermore, YKL-40 was demonstrated to stimulate TGF-[beta]1 production in malignant cells via interleukin-13 receptor [alpha]2- (IL-13R[alpha]2-) dependent mechanism (Figure 14). The binding of YKL-40 to IL-13R[alpha]2 results in the activation of MAPK, AKT, and Wnt/[beta]-catenin which play an important role in inhibiting apoptosis and interleukin-1[beta] (IL-1[beta]) production thereby acting as a potential cancer promoter [220].

Recently, Low et al. [221] showed that YKL-40 can also bind surface receptor for advanced glycation end product (RAGE), which is involved in tumor cell proliferation, migration, and survival through [beta]-catenin- and nuclear factor kappa-B- (NF-[kappa]B-) associated signaling pathways [221,222].

Most of the ongoing researches have been carried out on SNP rs4950928 in the promoter region of CHI3L1 gene as it was found to be associated with the serum/plasma YKL-40 levels [223, 224] and diseases such as asthma, bronchial hyperresponsiveness [207], and the severity of hepatitis C virus-induced liver fibrosis [225]. Some of the association studies of CHI3L1 SNPs with different diseases are shown in Table 15.

https://doi.org/10.1155/2018/9853192

Conflicts of Interest

The authors declare that they have no conflict of interest.

References

[1] A. Jemal, F. Bray, M. M. Center, J. Ferlay, E. Ward, and D. Forman, "Global cancer statistics," CA: A Cancer Journal for Clinicians, vol. 61, no. 2, pp. 69-90, 2011.

[2] A. Tenesa and M. G. Dunlop, "New insights into the aetiology of colorectal cancer from genome-wide association studies," Nature Reviews Genetics, vol. 10, no. 6, pp. 353-358, 2009.

[3] L. A. Torre, F. Bray, R. L. Siegel, J. Ferlay, J. Lortet-tieulent, and A. Jemal, "Global cancer statistics, 2012," CA: A Cancer Journal of Clinicians, vol. 65, no. 2, pp. 87-108, 2015.

[4] J. Bogaert and H. Prenen, "Molecular genetics of colorectal cancer," Annals of Gastroenterology, vol. 27, no. 1, pp. 9-14, 2014.

[5] C. M. Hutter, J. Chang-Claude, M. L. Slattery et al., "Characterization of gene-environment interactions for colorectal cancer susceptibility loci," Cancer Research, vol. 72, no. 8, pp. 2036-2044, 2012.

[6] C. M. Johnson, C. Wei, J. E. Ensor et al., "Meta-analyses of colorectal cancer risk factors," Cancer causes & control, vol. 24, no. 6, pp. 1207-1222, 2013.

[7] A. de la Chapelle, "Genetic predisposition to colorectal cancer," Nature Reviews Cancer, vol. 4, no. 10, pp. 769-780, 2004.

[8] P. J. Tarraga Lopez, J. S. Albero, and J. A. Rodriguez-Montes, "Primary and secondary prevention of colorectal cancer," Clinical Medicine Insights: Gastroenterology, vol. 7, 2014.

[9] W. M. Grady, "Genetic testing for high-risk colon cancer patients," Gastroenterology, vol. 124, no. 6, pp. 1574-1594, 2003.

[10] M. L. Slattery, J. D. Potter, K. N. Ma, B. J. Caan, M. Leppert, and W. Samowitz, "Western diet, family history of colorectal cancer, NAT2, GSTM-1 and risk of colon cancer," Cancer causes & control, vol. 11, no. 1, pp. 1-8, 2000.

[11] J. Terzic, S. Grivennikov, E. Karin, and M. Karin, "Inflammation and colon cancer," Gastroenterology, vol. 138, no. 6, pp. 2101-2114.e5, 2010.

[12] M. Koenig and J. B. Schofield, "The pathology of colorectal polyps and cancers," Surgery, vol. 29, no. 1, pp. 11 -14, 2011.

[13] J. A. Chavez and S. a. Summers, "Lipid oversupply, selective insulin resistance, and lipotoxicity: molecular mechanisms," Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, vol. 1801, no. 3, pp. 252-265, 2010.

[14] R. R. Huxley, A. Ansary-Moghaddam, P. Clifton, S. Czernichow, C. L. Parr, and M. Woodward, "The impact of dietary and lifestyle risk factors on risk of colorectal cancer: a quantitative overview of the epidemiological evidence," International Journal of Cancer, vol. 125, no. 1, pp. 171 180, 2009.

[15] S. S. Hecht, "Tobacco smoke carcinogens and lung cancer," Journal of National Cancer Institute, vol. 91, no. 14, pp. 1194-1210, 1999.

[16] D. A. Gutierrez, M. J. Puglisi, and A. H. Hasty, "Impact of increased adipose tissue mass on inflammation, insulin resistance, and dyslipidemia," Current Diabetes Reports, vol. 9, no. 1, pp. 26-32, 2009.

[17] A. Kumor, P. Daniel, M. Pietruczuk, and E. Malecka-Panas, "Serum leptin, adiponectin, and resistin concentration in colorectal adenoma and carcinoma (CC) patients," International Journal of Colorectal Disease, vol. 24, no. 3, pp. 275281, 2009.

[18] H. K. Seitz and F. Stickel, "Molecular mechanisms of alcohol-mediated carcinogenesis," Nature Reviews Cancer, vol. 7, no. 8, pp. 599-612, 2007.

[19] B. Vogelstein, E. R. Fearon, S. R. Hamilton et al., "Genetic alternations during colorectal tumor development," The New England Journal of Medicine, vol. 319, no. 9, pp. 525532, 1988.

[20] A. S. Sameer, "Colorectal cancer: molecular mutations and polymorphisms," Frontiers in Oncology, vol. 3, p. 114, 2013.

[21] A. Chan and E. Giovannucci, "Primary prevention of colorectal cancer," Gastroenterology, vol. 138, no. 6, pp. 20292043.e10, 2010.

[22] P. A. Vargas and D. S. Alberts, "Primary prevention of colorectal cancer through dietary modification," Cancer, vol. 70, no. 5, pp. 1229-1235, 1991.

[23] D. S. M. Chan, D. Aune, and T. Norat, "Red meat intake and colorectal cancer risk: a summary of epidemiological studies," Current Nutrition Reports, vol. 2, no. 1, pp. 56-62, 2012.

[24] K. Y. Wolin, Y. Yan, G. A. Colditz, and I.-M. Lee, "Physical activity and colon cancer prevention: a meta-analysis," British Journal of Cancer, vol. 100, no. 4, pp. 611-616, 2009.

[25] S.-Y. Kim, T.-W. Jun, Y.-S. Lee, H.-K. Na, Y.-J. Surh, and W. Song, "Effects of exercise on cyclooxygenase-2 expression and nuclear factor-[kappa]B DNA binding in human peripheral blood mononuclear cells," Annals of the New York Academy of Sciences, vol. 1171, no. 1, pp. 464-471, 2009.

[26] D. Wang and R. N. DuBois, "The role of COX-2 in intestinal inflammation and colorectal cancer," Oncogene, vol. 29, no. 6, pp. 781-788, 2010.

[27] J. E. Allison, L. C. Sakoda, T. R. Levin et al., "Screening for colorectal neoplasms with new fecal occult blood tests: update on performance characteristics," Journal of the National Cancer Institute, vol. 99, no. 19, pp. 1462-1470, 2007.

[28] M. Beg, M. Singh, M. Saraswat, and B. Rewar, "Occult gastrointestinal bleeding: detection, interpretation, and evaluation," Journal, Indian Academy of Clinical Medicine, vol. 3, no. 2, pp. 153-158, 2002.

[29] F. Stracci, M. Zorzi, and G. Grazzini, "Colorectal cancer screening: tests, strategies, and perspectives," Frontiers in Public Health, vol. 2, p. 210, 2014.

[30] W. S. Atkin, R. Edwards, I. Kralj-Hans et al., "Once-only flexible sigmoidoscopy screening in prevention of colorectal cancer: a multicentre randomised controlled trial," The Lancet, vol. 375, no. 9726, pp. 1624-1633, 2010.

[31] H. Brenner, M. Hoffmeister, V. Arndt, C. Stegmaier, L. Altenhofen, and U. Haug, "Protection from right- and left-sided colorectal neoplasms after colonoscopy: population-based study," Journal of the National Cancer Institute, vol. 102, no. 2, pp. 89-95, 2010.

[32] A. Trichopoulou, P. Lagiou, H. Kuper, and D. Trichopoulos, "Cancer and Mediterranean dietary traditions," Cancer Epidemiology Biomarkers & Prevention, vol. 9, no. 9, pp. 869-873, 2000.

[33] J. Shannon, E. White, A. L. Shattuck, and J. D. Potter, "Relationship of food groups and water intake to colon cancer risk," Cancer Epidemiology, Biomarkers & Prevention, vol. 5, no. 7, pp. 495-502, 1996.

[34] F. E. Ahmed, "Effect of diet, life style, and other environmental/chemopreventive factors on colorectal cancer development, and assessment of the risks," Journal of Environmental Science and Health, vol. 22, no. 2, pp. 91-148, 2004.

[35] D. Scharlau, A. Borowicki, N. Habermann et al., "Mechanisms of primary cancer prevention by butyrate and other products formed during gut flora-mediated fermentation of dietary fibre," Mutation Research/Reviews in Mutation Research, vol. 682, no. 1, pp. 39-53, 2009.

[36] A. A. Feregrino-Perez, L. C. Berumen, G. Garcia-Alcocer et al., "Composition and chemopreventive effect of polysaccharides from common beans (Phaseolus vulgaris L.) on azoxymethane-induced colon cancer," Journal of Agricultural and Food Chemistry, vol. 56, no. 18, pp. 8737-8744, 2008.

[37] J. A. T. Pennington and R. A. Fisher, "Classification of fruits and vegetables," Journal of Food Composition and Analysis, vol. 22, pp. S23-S31, 2009.

[38] S. C. Larsson, M. Kumlin, M. Ingelman-sundberg, and A. Wolk, "Dietary long-chain n-3 fatty acids for the prevention of cancer: a review of potential mechanisms," The American Journal of Clinical Nutrition, vol. 79, no. 6, pp. 935-945, 2004.

[39] L. M. Sanders, C. E. Henderson, M. Y. Hong et al., "An increase in reactive oxygen species by dietary fish oil coupled with the attenuation of antioxidant defenses by dietary pectin enhances rat colonocyte apoptosis," The Journal of Nutrition, vol. 134, no. 12, pp. 3233-3238, 2004.

[40] J. Vanamala, A. Glagolenko, P. Yang et al., "Dietary fish oil and pectin enhance colonocyte apoptosis in part through suppression of PPAR5/PGE 2 and elevation of PGE 3," Carcinogenesis, vol. 29, no. 4, pp. 790-796, 2008.

[41] L. Maintz and N. Novak, "Histamine and histamine intolerance," American journal of clinical nutrition, vol. 85, no. 5, pp. 1185-1196, 2007.

[42] S. J. Duthie, "Folate and cancer: how DNA damage, repair and methylation impact on colon carcinogenesis," Journal of Inherited Metabolic Disease, vol. 34, no. 1, pp. 101-109, 2011.

[43] H. J. Powers, "Interaction among folate, riboflavin, genotype, and cancer, with reference to colorectal and cervical cancer," The Journal of Nutrition, vol. 135, no. 12, pp. 2960S-2966S, 2005.

[44] M. Buset, M. Lipkin, S. Winawer, S. Swaroop, and E. Friedman, "Inhibition of human colonic epithelial cell proliferation in vivo and in vitro by calcium," Cancer Research, vol. 46, no. 10, pp. 5426-5430, 1986.

[45] K. Wu, W. C. Willett, C. S. Fuchs, G. A. Colditz, and E. L. Giovannucci, "Calcium intake and risk of colon cancer in women and men," Journal of the National Cancer Institute, vol. 94, no. 6, pp. 437-446, 2002.

[46] V. Fedirko, R. M. Bostick, W. D. Flanders et al., "Effects of vitamin D and calcium supplementation on markers of apoptosis in normal colon mucosa: a randomized, double-blind, placebo-controlled clinical trial," Cancer Prevention Research, vol. 2, no. 3, pp. 213-223, 2009.

[47] V. Fedirko, R. M. Bostick, W. D. Flanders et al., "Effects of vitamin D and calcium on proliferation and differentiation in normal colon mucosa: a randomized clinical trial," Cancer Epidemiology Biomarkers & Prevention, vol. 18, no. 11, pp. 2933-2941, 2009.

[48] O. Leimar, "Environmental and genetic cues in the evolution of phenotypic polymorphism," Evolutionary Ecology, vol. 23, no. 1, pp. 125-135, 2009.

[49] M. A. Chester and M. L. Olsson, "The ABO blood group gene: a locus of considerable genetic diversity," Transfusion Medicine Reviews, vol. 15, no. 3, pp. 177-200, 2001.

[50] C. A. Dick, J. Buenrostro, T. Butler, M. L. Carlson, D. J. Kliebenstein, and J. B. Whittall, "Arctic mustard flower color polymorphism controlled by petal-specific downregulation at the threshold of the anthocyanin biosynthetic pathway," PLoS One, vol. 6, no. 4, article e18230, 2011.

[51] H. Harris and D. A. Hopkinson, "Average heterozygosity per locus in man: an estimate based on the incidence of enzyme polymorphisms," Annals of Human Genetics, vol. 36, no. 1, pp. 9-20, 1972.

[52] R. C. Lewontin, "Twenty-five years ago in genetics: electrophoresis in the development of evolutionary genetics: milestone or millstone?," Genetics, vol. 128, no. 4, pp. 657-662, 1991.

[53] J. L. Hubby and R. C. Lewontin, "A molecular approach to the study of genic heterozygosity in natural populations. I. The number of alleles at different loci in Drosophila pseudoobscura," Genetics, vol. 54, no. 2, pp. 577-594, 1966.

[54] F. S. Collins, L. D. Brooks, and A. Chakravarti, "A DNA polymorphism discovery resource for research on human genetic variation," Genome Research, vol. 8, no. 12, pp. 1229-1231, 1998.

[55] A. Hamosh, T. M. King, B. J. Rosenstein et al., "Cystic fibrosis patients bearing both the common missense mutation, Gly^Asp at codon 551 and the [DELTA]F508 mutation are clinically indistinguishable from [DELTA]F508 homozygotes, except for decreased risk of meconium ileus," American Journal of Human Genetics, vol. 51, no. 2, pp. 245-250, 1992.

[56] A. B. Wolf, R. J. Caselli, E. M. Reiman, and J. Valla, "APOE and neuroenergetics: an emerging paradigm in Alzheimer's disease," Neurobiology of Aging, vol. 34, no. 4, pp. 1007-1017, 2013.

[57] Z. E. Sauna, C. Kimchi-Sarfaty, S. V. Ambudkar, and M. M. Gottesman, "Silent polymorphisms speak: how they affect pharmacogenomics and the treatment of cancer," Cancer Research, vol. 67, no. 20, pp. 9609-9612, 2007.

[58] C. Kimchi-Sarfaty, J. M. Oh, I.-W. Kim et al., "A "silent" polymorphism in the MDR1 gene changes substrate specificity," Science, vol. 315, no. 5811, pp. 525-528, 2007.

[59] M. Al-Haggar, A. Madej-Pilarczyk, L. Kozlowski et al., "A novel homozygous p.Arg527Leu LMNA mutation in two unrelated Egyptian families causes overlapping mandibuloacral dysplasia and progeria syndrome," European journal of human genetics, vol. 20, no. 11, pp. 1134-1140, 2012.

[60] S. K. Cordovado, M. Hendrix, C. N. Greene et al., "CFTR mutation analysis and haplotype associations in CF patients," Molecular Genetics and Metabolism, vol. 105, no. 2, pp. 249-254, 2012.

[61] B. Modrek and C. Lee, "A genomic view of alternative splicing," Nature Genetics, vol. 30, no. 1, pp. 13-19, 2002.

[62] M. Fareed and M. Afzal, "Single nucleotide polymorphism in genome-wide association of human population: a tool for broad spectrum service," Egyptian Journal of Medical Human Genetics, vol. 14, no. 2, pp. 123-134, 2012.

[63] S. Kim and A. Misra, "SNP genotyping: technologies and biomedical applications," Annual Review of Biomedical Engineering, vol. 9, no. 1, pp. 289-320, 2007.

[64] D. Botstein, R. L. White, M. Skolnick, and R. W. Davis, "Construction of a genetic linkage map in man using restriction fragment length polymorphisms," American Journal of Human Genetics, vol. 32, no. 3, pp. 314-331, 1980.

[65] P. Ross, L. Hall, I. Smirnov, and L. Haff, "High level multiplex genotyping by MALDI-TOF mass spectrometry," Nature Biotechnology, vol. 16, no. 13, pp. 1347-1351, 1998.

[66] K. J. Livak, "Allelic discrimination using fluorogenic probes and the 5' nuclease assay," Genetic Analysis - Biomolecular Engineering, vol. 14, no. 5-6, pp. 143-149, 1999.

[67] A. K. Tong, Z. Li, G. S. Jones, J. J. Russo, and J. Ju, "Combinatorial fluorescence energy transfer tags for multiplex biological assays," Nature Biotechnology, vol. 19, no. 8, pp. 756-759, 2001.

[68] P. Vineis, P. Brennan, F. Canzian et al., "Expectations and challenges stemming from genome-wide association studies," Mutagenesis, vol. 23, no. 6, pp. 439-444, 2008.

[69] C. S. Ku, E. Y. Loy, Y. Pawitan, and K. S. Chia, "The pursuit of genome-wide association studies: where are we now?," Journal of Human Genetics, vol. 55, no. 4, pp. 195-206, 2010.

[70] K. A. Frazer, D. G. Ballinger, D. R. Cox et al., "A second generation human haplotype map of over 3.1 million SNPs," Nature, vol. 449, no. 7164, pp. 851-861, 2007.

[71] J. N. Hirschhorn and M. J. Daly, "Genome-wide association studies for common diseases and complex traits," Nature Reviews Genetics, vol. 6, no. 2, pp. 95-108, 2005.

[72] T. A. Pearson and T. A. Manolio, "How to interpret a genome-wide association study," JAMA, vol. 299, no. 11, pp. 1335-1344, 2008.

[73] U. Peters, C. M. Hutter, L. Hsu et al., "Meta-analysis of new genome-wide association studies of colorectal cancer risk," Human Genetics, vol. 131, no. 2, pp. 217-234, 2012.

[74] P. Broderick, L. Carvajal-Carmona, A. M. Pittman et al., "A genome-wide association study shows that common alleles of SMAD7 influence colorectal cancer risk," Nature Genetics, vol. 39, no. 11, pp. 1315-1317, 2007.

[75] A. Tenesa, S. M. Farrington, J. G. D. Prendergast et al., "Genome-wide association scan identifies a colorectal cancer susceptibility locus on 11q23 and replicates risk loci at 8q24 and 18q21," Nature Genetics, vol. 40, no. 5, pp. 631-637, 2008.

[76] Q. Song, B. Zhu, W. Hu et al., "A common SMAD7 variant is associated with risk of colorectal cancer: evidence from a case-control study and a meta-analysis," PLoS One, vol. 7, no. 3, article e33318, 2012.

[77] I. Kirac, P. Matosevic, G. Augustin et al., "SMAD7 variant rs4939827 is associated with colorectal cancer risk in Croatian population," PLoS One, vol. 8, no. 9, article e74042,2013.

[78] L. Xing, Z. Wang, L. Jiang et al., "Matrix metalloproteinase-91562C>T polymorphism may increase the risk of lymphatic metastasis of colorectal cancer," Journal of Gastroenterology, vol. 13, no. 34, pp. 4626-4629, 2007.

[79] L. L. Xing, Z. N. Wang, L. Jiang et al., "Cyclooxygenase 2 polymorphism and colorectal cancer: -765G>C variant modifies risk associated with smoking and body mass index," World Journal of Gastroenterology, vol. 14, no. 11, pp. 1785-1789, 2008.

[80] Y.-H. Bai, H. Lu, D. Hong, C.-C. Lin, Z. Yu, and B.-C. Chen, "Vitamin D receptor gene polymorphisms and colorectal cancer risk: a systematic meta-analysis," World journal of gastroenterology, vol. 18, no. 14, pp. 1672-1679, 2012.

[81] S. J. Lubbe, A. M. Pittman, B. Olver et al., "The 14q22.2 colorectal cancer variant rs4444235 shows cis-acting regulation of BMP4," Oncogene, vol. 31, no. 33, pp. 3777-3784, 2012.

[82] C. Abbenhardt, E. M. Poole, R. J. Kulmacz et al., "Phospholipase A2G1B polymorphisms and risk of colorectal neoplasia," International journal of molecular epidemiology and genetics, vol. 4, no. 3, pp. 140-149, 2013.

[83] H. Yang, Y. Gao, T. Feng, T. B. Jin, L. L. Kang, and C. Chen, "Meta-analysis of the rs4779584 polymorphism and colorectal cancer risk," PLoS One, vol. 9, no. 2, article e89736, 2014.

[84] M. Li and Y. Gu, "Quantitative assessment of the influence of common variation rs16892766 at 8q23.3 with colorectal adenoma and cancer susceptibility," Molecular Genetics and Genomics, vol. 290, no. 2, pp. 461-469, 2015.

[85] C. G. Smith, D. Fisher, R. Harris et al., "Analyses of 7,635 patients with colorectal cancer using independent training and validation cohorts show that rs9929218 in CDH1 is a prognostic marker of survival," Clinical Cancer Research, vol. 21, no. 15, pp. 3453-3461, 2015.

[86] S. Wang, S. Wu, Q. Meng et al., "FAS rs2234767 and rs1800682 polymorphisms jointly contributed to risk of colorectal cancer by affecting SP1/STAT1 complex recruitment to chromatin," Scientific Reports, vol. 6, article 19229, 2016.

[87] X. Cao, S. Zhuang, Y. Hu, L. Xi, and L. Deng, "Associations between polymorphisms of long non-coding RNA MEG3 and risk of colorectal cancer in Chinese," Oncotarget, vol. 7, no. 14, pp. 19054-19059, 2016.

[88] G. Liu, D. Tu, M. Lewis et al., "Fc-[gamma] receptor polymorphisms, cetuximab therapy, and survival in the NCIC CTG CO.17 trial of colorectal cancer," Clinical Cancer Research, vol. 22, no. 10, pp. 2435-2444, 2016.

[89] C. Zeng, K. Matsuda, W.-H. Jia et al., "Identification of susceptibility loci and genes for colorectal cancer risk," Gastroenterology, vol. 150, no. 7, pp. 1633-1645, 2016.

[90] J. Li, J. Chang, J. Tian et al., "A rare variant P507L in TPP1 interrupts TPP1 -TIN2 interaction, influences telomere length, and confers colorectal cancer risk in Chinese population," Cancer Epidemiology Biomarkers & Prevention, vol. 27, no. 9, pp. 1029-1035, 2018.

[91] D. Zou, J. Lou, J. Ke et al., "Integrative expression quantitative trait locus-based analysis of colorectal cancer identified a functional polymorphism regulating SLC22A5 expression," European Journal of Cancer, vol. 93, no. 4, pp. 1-9, 2018.

[92] T. Shimizu, T. Nakai, K. Deguchi, K. Yamada, B. Yue, and J. Ye, "A polymorphic MYC response element in KBTBD11 influences colorectal cancer risk, especially in interaction with an MYC-regulated SNP rs6983267," Annals Oncology, vol. 29, no. 3, pp. 632-639, 2018.

[93] R. Sun, Y. Liang, F. Yuan et al., "Functional polymorphisms in the promoter region of miR-17-92 cluster are associated with a decreased risk of colorectal cancer," Oncotarget, vol. 8, no. 47, pp. 82531-82540, 2017.

[94] M. B. Sporn and A. B. Roberts, "Transforming growth factor-beta: recent progress and new challenges," The Journal of Cell Biology, vol. 119, no. 5, pp. 1017-1021, 1992.

[95] A. Nakao, M. Afrakhte, A. More, S. Itoh, M. Kawabata, and N. Heldin, "Identification of Smad7, a TGF[beta]-inducible antagonist of TGF-[beta] signalling," Nature, vol. 389, no. 6651, pp. 631-635, 1997.

[96] A. Chaudhury and P. H. Howe, "The tale of transforming growth factor-beta (TGFbeta) signaling: a soigne enigma," IUBMB Life, vol. 61, no. 10, pp. 929-939, 2009.

[97] S. Hong, H. J. Lee, S. J. Kim, and K. B. Hahm, "Connection between inflammation and carcinogenesis in gastrointestinal tract: focus on TGF-[beta] signaling," World Journal of Gastroenterology, vol. 16, no. 17, pp. 2080-2093, 2010.

[98] G. Monteleone, F. Pallone, and T. T. MacDonald, "Smad7 in TGF-[beta]-mediated negative regulation of gut inflammation," Trends in Immunology, vol. 25, no. 10, pp. 513-517, 2004.

[99] T. Fukushima, M. Mashiko, K. Takita et al., "Mutational analysis of TGF-beta type II receptor, Smad2, Smad3, Smad4, Smad6 and Smad7 genes in colorectal cancer," Journal of experimental & clinical cancer research, vol. 22, no. 2, pp. 315-320, 2003.

[100] S. K. Halder, R. D. Beauchamp, and P. K. Datta, "Smad7 induces tumorigenicity by blocking TGF-[beta]-induced growth inhibition and apoptosis," Experimental Cell Research, vol. 307, no. 1, pp. 231-246, 2005.

[101] A. B. Roberts, M. A. Anzano, L. C. Lamb, J. M. Smith, and M. B. Sporn, "New class of transforming growth factors potentiated by epidermal growth factor: isolation from nonneoplastic tissues," Proceedings of the National Academy of Sciences of the United States of America, vol. 78, no. 9, pp. 5339-5343, 1981.

[102] A. Roberts and L. Lamb, "Transforming growth factors: isolation of polypeptides from virally and chemically transformed cells by acid/ethanol extraction," Proceedings of the National Academy of Sciences of the United States of America, vol. 77, no. 6, pp. 3494-3498, 1980.

[103] H. Tsushima, S. Kawata, S. Tamura et al., "High levels of transforming growth factor beta 1 in patients with colorectal cancer: association with disease progression," Gastroenterology, vol. 110, no. 2, pp. 375-382, 1996.

[104] A. B. Roberts, N. L. Thompson, U. Heine, C. Flanders, and M. B. Sporn, "Transforming growth factor-[beta]: possible roles in carcinogenesis," British Journal of Cancer, vol. 57, pp. 594-600, 1988.

[105] F. Blanchette, R. Day, W. Dong, M. H. Laprise, and C. M. Dubois, "TGFbeta1 regulates gene expression of its own converting enzyme furin," The Journal of Clinical Investigation, vol. 99, no. 8, pp. 1974-1983, 1997.

[106] M. P. Schlunegger and M. G. Grutter, "An unusual feature revealed by the crystal structure at 2.2 A resolution of human transforming growth factor-[beta]2," Nature, vol. 358, no. 6385, pp. 430-434, 1992.

[107] J. Taipale, K. Miyazono, C. H. Heldin, and J. Keski-Oja, "Latent transforming growth factor-beta 1 associates to fibroblast extracellular matrix via latent TGF-beta binding protein," Journal of Cell Biology, vol. 124, no. 1, pp. 171-181, 1994.

[108] H. Hayashi and T. Sakai, "Biological significance of local TGF-[beta] activation in liver diseases," Frontiers in Physiology, vol. 3, p. 12, 2012.

[109] Z. Isogai, R. N. Ono, S. Ushiro et al., "Latent transforming growth factor [beta]-binding protein 1 interacts with fibrillin and is a microfibril-associated protein," Journal of Biological Chemistry, vol. 278, no. 4, pp. 2750-2757, 2003.

[110] P. Wipff and B. Hinz, "Integrins and the activation of latent transforming growth factor - an intimate relationship," European Journal of Cell Biology, vol. 87, no. 8-9, pp. 601-615, 2008.

[111] M. Gulubova, I. Manolova, J. Ananiev, A. Julianov, Y. Yovchev, and K. Peeva, "Role of TGF-[beta]1, its receptor TGF[beta]RII, and Smad proteins in the progression of colorectal cancer," International Journal of Colorectal Disease, vol. 25, no. 5, pp. 591-599, 2010.

[112] M. Laiho, J. A. DeCaprio, J. W. Ludlow, D. M. Livingston, and J. Massague, "Growth inhibition by TGF-[beta] linked to suppression of retinoblastoma protein phosphorylation," Cell, vol. 62, no. 1, pp. 175-185, 1990.

[113] G. J. Hannon and D. Beach, "p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest," Nature, vol. 371, no. 6494, pp. 257-261, 1994.

[114] I. Reynisdottir, K. Polyak, A. Iavarone, and J. Massague, "Kip/ Cip and Ink4 Cdk4 inhibitors cooperate to induce cell cycle arrest in response to TGF-beta," Genes and Development, vol. 9, no. 15, pp. 1831-1845, 1995.

[115] M. B. Datto, Y. Li, J. F. Panus, D. J. Howe, Y. Xiong, and X. F. Wang, "Transforming growth factor beta induces the cyclin-dependent kinase inhibitor p21 through a p53-independent mechanism," Proceedings of the National Academy of Sciences of the United States of America, vol. 92, no. 12, pp. 5545-5549, 1995.

[116] C. R. Chen, Y. Kang, P. M. Siegel, and J. Massague, "E2F4/5 and p107 as Smad cofactors linking the TGF[beta] receptor to c-myc repression," Cell, vol. 110, no. 1, pp. 19-32, 2002.

[117] C.-W. Jang, C.-H. Chen, C.-C. Chen, J. Chen, Y.-H. Su, and R.-H. Chen, "TGF-[beta] induces apoptosis through Smadmediated expression of DAP-kinase," Nature Cell Biology, vol. 4, no. 1, pp. 51-58, 2002.

[118] A. Ribeiro, S. F. Bronk, P. J. Roberts, R. Urrutia, and G.J. Gores, "The transforming growth factor /31--inducible transcription factor, TIEG1, mediates apoptosis through oxidative stress," Hepatology, vol. 30, no. 6, pp. 1490-1497, 1999.

[119] I. Tachibana, M. Imoto, P. N. Adjei et al., "Overexpression of the TGFbeta-regulated zinc finger encoding gene, TIEG, induces apoptosis in pancreatic epithelial cells," The Journal of Clinical Investigation, vol. 99, no. 10, pp. 2365-2374, 1997.

[120] G. Torre-Amione, R. D. Beauchamp, H. Koeppen et al., "A highly immunogenic tumor transfected with a murine transforming growth factor type beta 1 cDNA escapes immune surveillance," Proceedings of the National Academy of Sciences of the United States of America, vol. 87, no. 4, pp. 1486-1490, 1990.

[121] C. L. Arteaga, S. D. Hurd, A. R. Winnier, M. D. Johnson, B. M. Fendly, and J. T. Forbes, "Anti-transforming growth factor (TGF)-beta antibodies inhibit breast cancer cell tumorigenicity and increase mouse spleen natural killer cell activity. Implications for a possible role of tumor cell/host TGF-beta interactions in human breast cancer progression," Journal of Clinical Investigation, vol. 92, no. 6, pp. 2569-2576, 1993.

[122] R. Derynck, R. J. Akhurst, and A. Balmain, "TGF-[beta] signaling in tumor suppression and cancer progression," Nature Genetics, vol. 29, no. 2, pp. 117-129, 2001.

[123] Y. Kang, P. M. Siegel, W. Shu et al., "A multigenic program mediating breast cancer metastasis to bone," Cancer Cell, vol. 3, no. 6, pp. 537-549, 2003.

[124] L. Pertovaara, A. Kaipainen, T. Mustonen et al., "Vascular endothelial growth factor is induced in response to transforming growth factor-beta in fibroblastic and epithelial cells," Journal of biological chemistry, vol. 269, no. 9, pp. 6271-6274, 1994.

[125] J. M. Lee, "The epithelial-mesenchymal transition: new insights in signaling, development, and disease," Journal of Cell Biology, vol. 172, no. 7, pp. 973-981, 2006.

[126] R. Vogelmann, M.-D. Nguyen-Tat, K. Giehl, G. Adler, D. Wedlich, and A. Menke, "TGF[beta]-induced downregulation of E-cadherin-based cell-cell adhesion depends on PI3-kinase and PTEN," Journal of Cell Science, vol. 118, no. 20, pp. 4901-4912, 2005.

[127] H. Peinado, E. Ballestar, M. Esteller, and A. Cano, "Snail mediates E-cadherin repression by the recruitment of the Sin3A/histone deacetylase 1 (HDAC1)/HDAC2 complex," Molecular and Cellular Biology, vol. 24, no. 1, pp. 306-319, 2003.

[128] Q. Zhang, B. T. Helfand, T. L. Jang et al., "Nuclear factor-[beta]-mediated transforming growth factor-[beta]-induced expression of vimentin is an independent predictor of biochemical recurrence after radical prostatectomy," Clinical Cancer Research, vol. 15, no. 10, pp. 3557-3567, 2009.

[129] E. S. Radisky and D. C. Radisky, "Matrix metallo-proteinase-induced epithelial-mesenchymal transition in breast cancer," Journal of Mammary Gland Biology and Neoplasia, vol. 15, no. 2, pp. 201-212, 2010.

[130] P. M. Siegel and J. Massague, "Cytostatic and apoptotic actions of TGF-beta in homeostasis and cancer," Nature Reviews. Cancer, vol. 3, no. 11, pp. 807-820, 2003.

[131] P. Singh, J. D. Wig, and R. Srinivasan, "The Smad family and its role in pancreatic cancer," Indian Journal of Cancer, vol. 48, no. 3, pp. 351-360, 2011.

[132] R. Derynck and Y. E. Zhang, "Smad-dependent and Smad-independent pathways in TGF-beta family signalling," Nature, vol. 425, no. 6958, pp. 577-584, 2003.

[133] L. Yu, M. C. Hebert, and Y. E. Zhang, "TGF-[beta] receptor-activated p38 MAP kinase mediates Smad-independent TGF-[beta] responses," EMBO Journal, vol. 21, no. 14, pp. 3749-3759, 2002.

[134] N. A. Bhowmick, R. Zent, M. Ghiassi, M. McDonnell, and H. L. Moses, "Integrin j1 signaling is necessary for transforming growth factor-[beta] activation of p38MAPK and epithelial plasticity," Journal of Biological Chemistry, vol. 276, no. 50, pp. 46707-46713, 2001.

[135] M. Yamashita, K. Fatyol, C. Jin, X. Wang, Z. Liu, and Y. E. Zhang, "TRAF6 mediates Smad-independent activation of JNK and p38 by TGF-[beta]," Molecular Cell, vol. 31, no. 6, pp. 918-924, 2008.

[136] J. P. Thiery, "Epithelial-mesenchymal transitions in development and pathologies," Current Opinion in Cell Biology, vol. 15, no. 6, pp. 740-746, 2003.

[137] M. C. Wilkes, H. Mitchell, S. G. Penheiter et al., "Transforming growth factor-[beta][alpha]activation of phosphatidylinositol 3kinase is independent of Smad2 and Smad3 and regulates fibroblast responses via p21-activated kinase-2," Cancer Research, vol. 65, no. 22, pp. 10431-10440, 2005.

[138] I. Shin, A. V. Bakin, U. Rodeck, A. Brunet, and C. L. Arteaga, "Transforming growth factor [beta] enhances epithelial cell survival via Akt-dependent regulation of FKHRL1," Molecular Biology of the Cell, vol. 12, no. 11, pp. 3328-3339, 2001.

[139] A. B. Jaffe and A. Hall, "RHO GTPASES: biochemistry and biology," Annual Review of Cell and Developmental Biology, vol. 21, no. 1, pp. 247-269, 2005.

[140] Y. E. Zhang, "Non-Smad pathways in TGF-beta signaling," Cell Research, vol. 19, no. 1, pp. 128-139, 2009.

[141] L. Levy and C. S. Hill, "Alterations in components of the TGF-[beta] superfamily signaling pathways in human cancer," Cytokine & Growth Factor Reviews, vol. 17, no. 1-2, pp. 4158, 2006.

[142] W. M. Grady, L. L. Myeroff, S. E. Swinler et al., "Mutational inactivation of transforming growth factor [beta] receptor type II in microsatellite stable colon cancers," Cancer Research, vol. 59, no. 2, pp. 320-324, 1999.

[143] M. A. Lynch, R. Nakashima, H. Song et al., "Mutational analysis of the transforming growth factor [beta] receptor type II gene in human ovarian carcinoma," Cancer Research, vol. 58, no. 19, pp. 4227-4232, 1998.

[144] C. D. Lucke, A. Philpott, J. C. Metcalfe et al., "Inhibiting mutations in the transforming growth factor [beta] type 2 receptor in recurrent human breast cancer," Cancer Research, vol. 61, no. 2, pp. 482-485, 2001.

[145] I. Y. Kim, H. J. Ahn, S. Lang et al., "Loss of expression of transforming growth factor-beta receptors is associated with poor prognosis in prostate cancer patients," Clinical Cancer Research, vol. 4, no. 7, pp. 1625-1630, 1998.

[146] H. T. Zhang, X. F. Chen, M. H. Wang et al., "Defective expression of transforming growth factor [beta] receptor type II is associated with CpG methylated promoter in primary non-small cell lung cancer," Clinical Cancer Research, vol. 10, no. 7, pp. 2359-2367, 2004.

[147] H. Gobbi, C. L. Arteaga, R. A. Jensen et al., "Loss of expression of transforming growth factor beta type II receptor correlates with high tumour grade in human breast in-situ and invasive carcinomas," Histopathology, vol. 36, no. 2, pp. 168-177, 2000.

[148] T. Chen, J. Triplett, B. Dehner et al., "Transforming growth factor-[beta] receptor type I gene is frequently mutated in ovarian carcinomas," Cancer Research, vol. 61, no. 12, pp. 4679-4682, 2001.

[149] D. Wang, T. Kanuma, H. Mizunuma et al., "Analysis of specific gene mutations in the transforming growth factor-[beta] signal transduction pathway in human ovarian cancer," Journal of controlled release, vol. 60, no. 16, pp. 4507-4512, 2000.

[150] T. Chen, W. Yan, R. G. Wells et al., "Novel inactivating mutations of transforming growth factor-[beta] type I receptor gene in head-and-neck cancer metastases," International Journal of Cancer, vol. 93, no. 5, pp. 653-661, 2001.

[151] M. Goggins, M. Shekher, K. Turnacioglu, C. J. Yeo, R. H. Hruban, and S. E. Kern, "Genetic alterations of the transforming growth factor [beta] receptor genes in pancreatic and biliary adenocarcinomas," Cancer research, vol. 58, no. 23, pp. 5329-5332, 1998.

[152] L. A. Wolfraim, T. M. Fernandez, M. Mamura et al., "Loss of Smad3 in acute T-cell lymphoblastic leukemia," The New England Journal of Medicine, vol. 351, no. 6, pp. 552-559, 2004.

[153] N. I. Fleming, R. N. Jorissen, D. Mouradov et al., "SMAD2, SMAD3 and SMAD4 mutations in colorectal cancer," Cancer Research, vol. 73, no. 2, pp. 725-735, 2013.

[154] S. Thiagalingam, C. Lengauer, F. Leach et al., "Evaluation of candidate tumour suppressor genes on chromosome 18 in colorectal cancers," Nature Genetics, vol. 13, no. 3, pp. 343-346, 1996.

[155] J. L. Boulay, G. Mild, J. Reuter et al., "Combined copy status of 18q21 genes in colorectal cancer shows frequent retention of SMAD7," Genes, Chromosomes & Cancer, vol. 31, no. 3, pp. 240-247, 2001.

[156] H. Hayashi, S. Abdollah, Y. Qiu et al., "The MAD-related protein Smad7 associates with the TGF[beta] receptor and functions as an antagonist of TGF[beta] signaling," Cell, vol. 89, no. 7, pp. 1165-1173, 1997.

[157] P. Kavsak, R. K. Rasmussen, C. G. Causing et al., "Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGF[beta] receptor for degradation," Molecular cell, vol. 6, no. 6, pp. 1365-1375, 2000.

[158] X. Yan, H. Liao, M. Cheng et al., "Smad7 protein interacts with receptor-regulated Smads (R-Smads) to inhibit transforming growth factor-[beta] (TGF-[beta])/Smad signaling," Journal of Biological Chemistry, vol. 291, no. 1, pp. 382-392, 2016.

[159] S. Zhang, T. Fei, L. Zhang et al., "Smad7 antagonizes transforming growth factor [beta] signaling in the nucleus by interfering with functional Smad-DNA complex formation," Molecular and cellular biology, vol. 27, no. 12, pp. 4488-4499, 2007.

[160] C. Stolfi, I. Marafini, V. De Simone, F. Pallone, and G. Monteleone, "The dual role of Smad7 in the control of cancer growth and metastasis," International Journal of Molecular Sciences, vol. 14, no. 12, pp. 23774-23790, 2013.

[161] L. Ulloa, J. Doody, and J. Massague, "Inhibition of transforming growth factor-[beta]/SMAD signalling by the interferon-[gamma]/ STAT pathway," Nature, vol. 397, no. 6721, pp. 710-713, 1999.

[162] S. Edlund, S. Y. Lee, S. Grimsby et al., "Interaction between Smad7 and [beta]-Catenin: importance for transforming growth factor [beta]-induced apoptosis," Molecular and cellular biochemistry, vol. 25, no. 4, pp. 1475-1488, 2005.

[163] M. S. Yang, D. W. Morris, G. Donohoe et al., "Chitinase-3like 1 (CHI3L1) gene and schizophrenia: genetic association and a potential functional mechanism," Biological Psychiatry, vol. 64, no. 2, pp. 98-103, 2008.

[164] J.-L. Boulay, G. Mild, A. Lowy et al., "SMAD7 is a prognostic marker in patients with colorectal cancer," International journal of cancer, vol. 104, no. 4, pp. 446-449, 2003.

[165] C. Stolfi, V. De Simone, A. Colantoni et al., "A functional role for Smad7 in sustaining colon cancer cell growth and survival," Cell death & disease, vol. 5, no. 2, article e1073, 2014.

[166] C. L. Thompson, S. J. Plummer, L. S. Acheson, T. C. Tucker, G. Casey, and L. Li, "Association of common genetic variants in SMAD7 and risk of colon cancer," Carcinogenesis, vol. 30, no. 6, pp. 982-986, 2009.

[167] M. L. Slattery, J. Herrick, K. Curtin et al., "Increased risk of colon cancer associated with a genetic polymorphism of SMAD7," Cancer Research, vol. 70, no. 4, pp. 1479-1485, 2010.

[168] S. von Holst, S. Picelli, D. Edler et al., "Association studies on 11 published colorectal cancer risk loci," British journal of cancer, vol. 103, no. 4, pp. 575-580, 2010.

[169] Y. H. Loh, P. N. Mitrou, A. Wood et al., "SMAD7 and MGMT genotype variants and cancer incidence in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk Study," Cancer epidemiology, vol. 35, no. 4, pp. 369-374, 2011.

[170] X. Li, X.-X. Yang, N.-Y. Hu, J.-Z. Sun, F.-X. Li, and M. Li, "A risk-associated single nucleotide polymorphism of SMAD7 is common to colorectal, gastric, and lung cancers in a Han Chinese population," Molecular biology reports, vol. 38, no. 8, pp. 5093-5097, 2011.

[171] M. N. Passarelli, A. E. Coghill, C. M. Hutter et al., "Common colorectal cancer risk variants in SMAD7 are associated with survival among prediagnostic nonsteroidal anti-inflammatory drug users: a population-based study of postmenopausal women," Genes, Chromosomes & Cancer, vol. 50, no. 11, pp. 875-886, 2011.

[172] I. N. Mates, V. Jinga, I. E. Csiki et al., "Single nucleotide polymorphisms in colorectal cancer: associations with tumor site and TNM stage," Journal of Gastrointestinal and Liver Diseases, vol. 21, no. 1, pp. 45-52, 2012.

[173] X. Garcia-Albeniz, H. Nan, L. Valeri et al., "Phenotypic and tumor molecular characterization of colorectal cancer in relation to a susceptibility SMAD7 variant associated with survival," Carcinogenesis, vol. 34, no. 2, pp. 292-298, 2013.

[174] S. Noci, M. Dugo, F. Bertola et al., "A subset of genetic susceptibility variants for colorectal cancer also has prognostic value," The Pharmacogenomics Journal, vol. 16, no. 2, pp. 173-179, 2015.

[175] K. J. Jung, D. Won, C. Jeon et al., "A colorectal cancer prediction model using traditional and genetic risk scores in Koreans," BMC genetics, vol. 16, no. 1, pp. 1-7, 2015.

[176] A. Abuli, A. Castells, L. Bujanda et al., "Genetic variants associated with colorectal adenoma susceptibility," PLoS One, vol. 11, no. 4, article e0153084, 2016.

[177] S. Baert-Desurmont, F. Charbonnier, E. Houivet et al., "Clinical relevance of 8q23, 15q13 and 18q21 SNP genotyping to evaluate colorectal cancer risk," European Journal of Human Genetics, vol. 24, no. 1, pp. 99-105, 2015.

[178] J. S. Johansen, M. K. Williamson, J. S. Rice, and P. A. Price, "Identification of proteins secreted by human osteoblastic cells in culture," Journal of Bone and Mineral Research, vol. 7, no. 5, pp. 501-512, 1992.

[179] B. E. Hakala, C. White, and A. D. Recklies, "Human cartilage gp-39, a major secretory product of articular chondrocytes and synovial cells, is a mammalian member of a chitinase protein family," Journal of Biological Chemistry, vol. 268, no. 34, pp. 25803-25810, 1993.

[180] L. M. Shackelton, D. M. Mann, and A. J. T. Millis, "Identification of a 38-kDa heparin-binding glycoprotein (gp38k) in differentiating vascular smooth muscle cells as a member of a group of proteins associated with tissue remodeling," Journal of Biological Chemistry, vol. 270, no. 22, pp. 13076-13083, 1995.

[181] S. Harvey, M. Weisman, J. O'Dell et al., "Chondrex: new marker of joint disease," Clinical chemistry, vol. 44, no. 3, pp. 509-516, 1998.

[182] A. K. Mohanty, G. Singh, M. Paramasivam et al., "Crystal structure of a novel regulatory 40-kDa mammary gland protein (MGP-40) secreted during involution," Journal of Biological Chemistry, vol. 278, no. 16, pp. 14451-14460, 2003.

[183] M. Rehli, S. W. Krause, and R. Andreesen, "Molecular characterization of the gene for human cartilage gp-39 (CHI3L1), a member of the chitinase protein family and marker for late stages of macrophage differentiation," Genomics, vol. 43, no. 2, pp. 221-225, 1997.

[184] W. C. Buhi, "Characterization and biological roles of oviduct-specific, oestrogen-dependent glycoprotein," Reproduction, vol. 123, no. 3, pp. 355-362, 2002.

[185] B. Henrissat and A. Bairoch, "New families in the classification of glycosyl hydrolases based on amino acid sequence similarities," The Biochemical Journal, vol. 293, no. 3, pp. 781-788, 1993.

[186] G. H. Renkema, R. G. Boot, F. L. Au et al., "Chitotriosidase, a chitinase, and the 39-kDa human cartilage glycoprotein, a chitin-binding lectin, are homologues of family 18 glycosyl hydrolases secreted by human macrophages," European Journal of Biochemistry, vol. 251, no. 1-2, pp. 504-509, 1998.

[187] K. J. Kramer and D. Koga, "Insect chitin: physical state, synthesis, degradation and metabolic regulation," Insect Biochemistry, vol. 16, no. 6, pp. 851-877, 1986.

[188] C. Cintin, J. S. Johansen, I. J. Christensen, P. A. Price, S. Sorensen, and H. J. Nielsen, "Serum YKL-40 and colorectal cancer," British journal of cancer, vol. 79, no. 9-10, pp. 1494-1499, 1999.

[189] Y. Huang, M. Prasad, W. J. Lemon et al., "Gene expression in papillary thyroid carcinoma reveals highly consistent profiles," Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 26, pp. 15044-15049, 2001.

[190] B. V. Jensen, J. S. Johansen, and P. A. Price, "High levels of serum HER-2/neu and YKL-40 independently reflect aggressiveness of metastatic breast cancer," vol. 9, no. 12, pp. 4423-4434, 2003.

[191] H. Dehn, E. V. S. H0gdall, J. S. Johansen et al., "Plasma YKL-40, as a prognostic tumor marker in recurrent ovarian cancer," Acta Obstetricia et Gynecologica Scandinavica, vol. 82, no. 3, pp. 287-293, 2003.

[192] J. S. Johansen, L. Drivsholm, P. a. Price, and I. J. Christensen, "High serum YKL-40 level in patients with small cell lung cancer is related to early death," Lung cancer, vol. 46, no. 3, pp. 333-340, 2004.

[193] N. Fukushima, J. Koopmann, N. Sato et al., "Gene expression alterations in the non-neoplastic parenchyma adjacent to infiltrating pancreatic ductal adenocarcinoma," Modern pathology, vol. 18, no. 6, pp. 779-787, 2005.

[194] J. M. Nigro, A. Misra, L. Zhang et al., "Integrated array-comparative genomic hybridization and expression array profiles identify clinically relevant molecular subtypes of glioblastoma," Cancer Research, vol. 65, no. 5, pp. 1678-1686, 2005.

[195] M. K. Tanwar, M. R. Gilbert, and E. C. Holland, "Gene expression microarray analysis reveals YKL-40 to be a potential serum marker for malignant character in human glioma," Cancer Research, vol. 62, no. 15, pp. 4364-4368, 2002.

[196] A. Lal, A. E. Lash, S. F. Altschul et al., "A public database for gene expression in human cancers," Cancer Research, vol. 59, no. 21, pp. 5403-5407, 1999.

[197] S. Thongsom, W. Chaocharoen, A. Silsirivanit et al., "YKL-40/chitinase-3-like protein 1 is associated with poor prognosis and promotes cell growth and migration of cholangiocarcinoma," Tumour biology, vol. 37, no. 7, pp. 9451-9463, 2016.

[198] M. Prakash, M. Bodas, D. Prakash et al., "Diverse pathological implications of YKL-40: answers may lie in 'outside-in' signaling," Cellular signalling, vol. 25, no. 7, pp. 1567-1573, 2013.

[199] C. G. Lee, D. Hartl, G. R. Lee et al., "Role of breast regression protein 39 (BRP-39)/chitinase 3-like-1 in Th2 and IL-13induced tissue responses and apoptosis," Journal of Experimental Medicine, vol. 206, no. 5, pp. 1149-1166, 2009.

[200] G. Kronborg, C. 0stergaard, N. Weis et al., "Serum level of YKL-40 is elevated in patients with streptococcus pneumoniae bacteremia and is associated with the outcome of the disease," Scandinavian Journal of Infectious Diseases, vol. 34, no. 5, pp. 323-326, 2002.

[201] J. S. Johansen, "Studies on serum YKL-40 as a biomarker in diseases with inflammation, tissue remodelling, fibroses and cancer," Danish Medical Bulletin, vol. 53, no. 2, pp. 172-209, 2006.

[202] J. S. Johansen, P. Christoffersen, S. M0ller et al., "Serum YKL40 is increased in patients with hepatic fibrosis," Journal of hepatology, vol. 32, no. 6, pp. 911-920, 2000.

[203] B. Combe, M. Dougados, P. Goupille et al., "Prognostic factors for radiographic damage in early rheumatoid arthritis: a multiparameter prospective study," Arthritis & Rheumatism, vol. 44, no. 8, pp. 1736-1743, 2001.

[204] M. Abe, M. Takahashi, K. Naitou, K. Ohmura, and A. Nagano, "Investigation of generalized osteoarthritis by combining X-ray grading of the knee, spine and hand using biochemical markers for arthritis in patients with knee osteoarthritis," Clinical Rheumatology, vol. 22, no. 6, pp. 425-431, 2003.

[205] I. Vind, J. S. Johansen, P. a. Price, and P. Munkholm, "Serum YKL-40, a potential new marker of disease activity in patients with inflammatory bowel disease," Scandinavian Journal of Gastroenterology, vol. 38, no. 6, pp. 599-605, 2003.

[206] J. S. Johansen, N. Milman, M. Hansen, C. Garbarsch, P. A. Price, and N. Graudal, "Increased serum YKL-40 in patients with pulmonary sarcoidosis--a potential marker of disease activity?," Respiratory Medicine, vol. 99, no. 4, pp. 396-402, 2005.

[207] C. Ober, Z. Tan, Y. Sun et al., "Effect of variation in CHI3L1 on serum YKL-40 level, risk of asthma, and lung function," The New England Journal of Medicine, vol. 358, no. 16, pp. 1682-1691, 2008.

[208] K. Brasso, I. J. Christensen, J. S. Johansen et al., "Prognostic value of PINP, bone alkaline phosphatase, CTX-I, and YKL40 in patients with metastatic prostate carcinoma," The Prostate, vol. 66, no. 5, pp. 503-513, 2006.

[209] J. S. Johansen, C. Cintin, M. J0rgensen, C. Kamby, and P. A. Price, "Serum YKL-40: a new potential marker of prognosis and location of metastases of patients with recurrent breast cancer," European Journal of Cancer, vol. 31, no. 9, pp. 1437-1442, 1995.

[210] C. Cintin, J. S. Johansen, I. J. Christensen, P. A. Price, S. S0rensen, and H. J. Nielsen, "High serum YKL-40 level after surgery for colorectal carcinoma is related to short survival," Cancer, vol. 95, no. 2, pp. 267-274, 2002.

[211] J. S. Johansen, I. J. Christensen, R. Riisbro et al., "High serum YKL-40 levels in patients with primary breast cancer is related to short recurrence free survival," Breast Cancer Research and Treatment, vol. 80, no. 1, pp. 15-21, 2003.

[212] E. V. S. H0gdall, M. Ringsholt, C. K. H0gdall et al., "YKL-40 tissue expression and plasma levels in patients with ovarian cancer," BMC Cancer, vol. 9, no. 1, p. 8, 2009.

[213] J. Kzhyshkowska, S. Yin, T. Liu, V. Riabov, and I. Mitrofanova, "Role of chitinase-like proteins in cancer," Biological Chemistry, vol. 397, no. 3, pp. 231-247, 2016.

[214] R. Shao, K. Hamel, L. Petersen et al., "YKL-40, a secreted glycoprotein, promotes tumor angiogenesis," Oncogene, vol. 28, no. 50, pp. 4456-4468, 2009.

[215] F. Fusetti, T. Pijning, K. H. Kalk, E. Bos, and B. W. Dijkstra, "Crystal structure and carbohydrate-binding properties of the human cartilage glycoprotein-39," Journal of Biological Chemistry, vol. 278, no. 39, pp. 37753-37760, 2003.

[216] T. Maeda, J. Desouky, and A. Friedl, "Syndecan-1 expression by stromal fibroblasts promotes breast carcinoma growth in vivo and stimulates tumor angiogenesis," Oncogene, vol. 25, no. 9, pp. 1408-1412, 2006.

[217] K. J. McQuade, D. M. Beauvais, B. J. Burbach, and A. C. Rapraeger, "Syndecan-1 regulates avfi5 integrin activity in B82L fibroblasts," Journal of Cell Science, vol. 119, no. 12, pp. 2445-2456, 2006.

[218] S. Libreros, R. Garcia-Areas, and V. Iragavarapu-Charyulu, "CHI3L1 plays a role in cancer through enhanced production of pro-inflammatory/pro-tumorigenic and angiogenic factors," Immunologic research, vol. 57, no. 1-3, pp. 99-105, 2013.

[219] R. A. Francescone, S. Scully, M. Faibish et al., "Role of YKL-40 in the angiogenesis, radioresistance, and progression of glioblastoma," Journal of Biological Chemistry, vol. 286, no. 17, pp. 15332-15343, 2011.

[220] C. H. He, C. G. Lee, C. S. Dela Cruz et al., "Chitinase 3-like 1 regulates cellular and tissue responses via IL-13 receptor [alpha]2," Cell Reports, vol. 4, no. 4, pp. 830-841, 2013.

[221] D. Low, R. Subramaniam, L. Lin et al., "Chitinase 3-like 1 induces survival and proliferation of intestinal epithelial cells during chronic inflammation and colitis-associated cancer by regulating S100A9," Oncotarget, vol. 6, no. 34, pp. 36535-36550, 2015.

[222] P. Malik, N. Chaudhry, R. Mittal, and T. K. Mukherjee, "Role of receptor for advanced glycation end products in the complication and progression of various types of cancers," Biochimica et Biophysica Acta (BBA)--General Subjects, vol. 1850, no. 9, pp. 1898-1904, 2015.

[223] A. D. Kjaergaard, J. S. Johansen, B. G. Nordestgaard, and S. E. Bojesen, "Genetic variants in CHI3L1 influencing YKL-40 levels: resequencing 900 individuals and genotyping 9000 individuals from the general population," Journal of Medical Genetics, vol. 50, no. 12, pp. 831-837, 2013.

[224] X. Zhao, R. Tang, B. Gao et al., "Functional variants in the promoter region of chitinase 3-like 1 (CHI3L1) and susceptibility to schizophrenia," AJHG, vol. 80, no. 1, pp. 12-18, 2007.

[225] M.-L. Berres, S. Papen, K. Pauels et al., "A functional variation in CHI3L1 is associated with severity of liver fibrosis and YKL-40 serum levels in chronic hepatitis C infection," Journal of Hepatology, vol. 50, no. 2, pp. 370-376, 2009.

[226] A. Kruit, J. C. Grutters, H. J. T. Ruven, C. C. M. van Moorsel, and J. M. M. van den Bosch, "A CHI3L1 gene polymorphism is associated with serum levels of YKL-40, a novel sarcoidosis marker," Respiratory Medicine, vol. 101, no. 7, pp. 1563-1571, 2007.

[227] B. Boisselier, Y. Marie, S. El Hallani et al., "No association of (-131C[right arrow]G) variant of CHI3L1 gene with risk of glioblastoma and prognosis," Journal of Neuro-Oncology, vol. 94, no. 2, pp. 169-172, 2009.

[228] C. N. Rathcke, J. Holmkvist, L. L. N. Husmoen et al., "Association of polymorphisms of the CHI3L1 gene with asthma and atopy: a populations-based study of 6514 Danish adults," PLoS One, vol. 4, no. 7, article e6106, 2009.

[229] K. R. Nielsen, R. Steffensen, M. Boegsted et al., "Promoter polymorphisms in the chitinase 3-like 1 gene influence the serum concentration of YKL-40 in Danish patients with rheumatoid arthritis and in healthy subjects," Arthritis Research & Therapy, vol. 13, no. 3, article R109, 2011.

[230] F. Xie, Q. Qian, Z. Chen, G. Ma, and Y. Feng, "Chitinase 3like 1 gene-329G/A polymorphism, plasma concentration and risk of coronary heart disease in a Chinese population," Gene, vol. 499, no. 1, pp. 135-138, 2012.

[231] H. Yamamori, R. Hashimoto, K. Ohi et al., "A promoter variant in the chitinase 3-like 1 gene is associated with serum YKL-40 level and personality trait," Neuroscience letters, vol. 513, no. 2, pp. 204-208, 2012.

[232] K. M. A. Henningsen, M. S. Olesen, G. Sajadieh, S. Haunsoe, and J. H. Svendsen, "A polymorphism associated with increased levels of YKL-40 and the risk of early onset of lone atrial fibrillation," Journal of Negative Results in Biomedicine, vol. 12, no. 1, p. 1, 2013.

[233] H. Ortega, C. Prazma, R. Y. Suruki, H. Li, and W. H. Anderson, "Association of CHI3L1 in African-Americans with prior history of asthma exacerbations and stress," Journal of asthma, vol. 50, no. 1, pp. 7-13, 2013.

[234] Y.-S. Lin, Y.-F. Liu, Y.-E. Chou et al., "Correlation of chitinase 3-like 1 single nucleotide polymorphisms and haplotypes with uterine cervical cancer in Taiwanese women," PLoS One, vol. 9, article e104038, no. 9, 2014.

[235] Y. Tsai, Y. Ko, M. Huang et al., "CHI3L1 polymorphisms associate with asthma in a Taiwanese population," BMC Medical Genetics, vol. 15, no. 1, p. 86, 2014.

[236] S. Wu, L.-A. Hsu, S.-T. Cheng et al., "Circulating YKL-40 level, but not CHI3L1 gene variants, is associated with atherosclerosis-related quantitative traits and the risk of peripheral artery disease," International Journal of Molecular Sciences, vol. 15, no. 12, pp. 22421-22437, 2014.

[237] S. Naglot and K. Dalal, "Association of CG genotype at rs4950928 promoter in CHI3L1 gene with YKL-40 levels and asthma susceptibility in North Indian asthma patients," Indian Journal of Clinical Biochemistry, vol. 30, no. 4, pp. 403-411,2015.

[238] K. R. Nielsen, R. Steffensen, M. D. Bendtsen et al., "Inherited inflammatory response genes are associated with B-cell non-Hodgkin's lymphoma risk and survival," PLoS One, vol. 10, no. 10, pp. e0139329-e0139318, 2015.

[239] A. J. James, L. E. Reinius, M. Verhoek et al., "Increased YKL-40 and chitotriosidase in asthma and chronic obstructive pulmonary disease," American Journal of Respiratory and Critical Care Medicine, vol. 193, no. 2, pp. 131-142, 2015.

[240] A. D. Kjaergaard, J. S. Johansen, S. E. Bojesen, and B. G. Nordestgaard, "Observationally and genetically high YKL40 and risk of venous thromboembolism in the general population: cohort and Mendelian randomization studies," Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 36, no. 5, pp. 1030-1036, 2016.

[241] K. Ting, K. Ueng, S. Yang, and P. Wang, "The association of YKL-40 genetic polymorphisms with coronary artery disease in Taiwan population," International Journal of Clinical and Experimental Medicineis, vol. 9, no. 2, pp. 4211-4221, 2016.

Amal Ahmed Abd El-Fattah, (1) Nermin Abdel Hamid Sadik, (1) Olfat Gamil Shaker, (2) and Amal Mohamed Kamal [ID] (1)

(1) Biochemistry Department, Faculty of Pharmacy, Cairo University, Kasr El-Einy Street, Cairo, Egypt

(2) Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Cairo University, Cairo, Egypt

Correspondence should be addressed to Amal Mohamed Kamal; amalmohamedkamal@yahoo.com

Received 17 May 2018; Revised 1 August 2018; Accepted 16 August 2018; Published 25 October 2018

Academic Editor: Vinod K. Mishra

Caption: Figure 2: Genetic contribution to CRC.

Caption: Figure 3: The colorectal adenoma-carcinoma sequence (Vogelstein model). Progression from normal epithelium through adenoma to CRC is characterized by accumulated abnormalities of multiple genes.

Caption: Figure 4: Genetic polymorphism in the coding region (http://academic.pgcc.edu/).

Caption: Figure 5: The sequential steps in the synthesis and secretion of active TGF-[beta].

Caption: Figure 6: Canonical and noncanonical pathways of TGF-[beta].

Caption: Figure 7: Gene constructions of SMADs

Caption: Figure 8: Smad7 antagonizes TGF-[beta] signaling in the cytoplasm and the nucleus, respectively [160].

Caption: Figure 9: Several synergistic and antagonistic factors modulate the regulatory functions of YKL-40. EGFR: epidermal growth factor receptor; SAPK: stress-activated protein kinases; MCP-1: monocyte chemoattractant protein-1.

Caption: Figure 10: YKL-40 regulates the pathogenesis of cancer and inflammatory disorders [198].

Caption: Figure 11: Role of inflammatory cytokines in YKL-40-mediated allergy and inflammation.

Caption: Figure 12: YKL-40 supports tumor progression.

Caption: Figure 13: Involvement of YKL-40 in pathways pertaining to cell proliferation, survival, differentiation, and tumorigenesis.

Caption: Figure 14: YKL-40 function through IL-13R[alpha]2-dependent mechanism.
Table 1: Genetic classification of CRC

Sporadic CRC           Familial CRC              Hereditary CRC

Occurs entirely by     Occurs when there         When people
chance throughout      are two or more           inherit a high
life without any       family members            penetrant gene
previous family        with a history            mutation from
history                of CRC                    either of their
                                                 parents
                       No specific inherited
                       gene mutation has
                       been identified to
                       explain the cancer yet.

-60%-80%               -15%-30%                  -5%

Table 2: Risk factors of CRC.

Nonmodifiable

(i) Age: the incidence of CRC diagnosis increases after the age of
40 and rises sharply after age 50, but there is an increase in the
young-onset rate due to the adoption of a Westernized lifestyle and
diet [9]

(ii) Family history of CRC (especially a first-degree relative
diagnosed at age 49 or younger) [10]

(iii) Hereditary predisposition

(a) Hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome)

(b) Familial adenomatous polyposis (FAP) [4, 9]

(iv) Inflammatory bowel disease (IBD): chronic inflammation is
assumed to underlie the cause of colitis-associated cancer, which
is associated with oxidative stress-induced DNA damage resulting in
the activation of procarcinogenic genes and silencing of
tumor-suppressor pathways [11]

(v) Adenomatous polyp: polyps are abnormal growths of the large
intestine lining that protrude into the intestinal lumen. Polyps
greater than one centimeter in diameter are associated with a
greater risk of cancer [12]

Modifiable

(i) Diets: Western diet rich in red meat, refined grains, desserts,
and low in fiber was reported to be associated with
increased CRC risk [10, 13, 14]

(ii) Cigarette smoking: carcinogens as aromatic amines,
nitrosamines, and polycyclic aromatic hydrocarbons in tobacco smoke
produce metabolites that can react with DNA or other macromolecules
to form DNA adducts inducing genetic mutations [15]

(iii) Obesity: obese women have higher risk of CRC than obese men
due to higher abdominal visceral adipose tissue volume
[16, 17]

(iv) High alcohol consumption (>2 glasses per day): ethanol
increases the activation of various procarcinogens present in
tobacco smoke, diets, and industrial chemicals to carcinogens
through the induction of CYP2E1 [18]

Table 3: Staging and survival of CRC.

Dukes'     TNM staging     Description                      Survival
staging                                                     (%)

           Stage 0         Carcinoma in situ

A          Stage I         No nodal involvement, no         90-100%
                           metastasis, tumor invades
                           submucosa ([T.sub.1]
                           [N.sub.0], [M.sub.0]), tumor
                           invades muscularis ([T.sub.2],
                           [N.sub.0], [M.sub.0])

B          Stage II        No nodal involvement, no         75-85%
                           metastasis, tumor invades
                           subserosa ([T.sub.3],
                           [N.sub.0], [M.sub.0]), invade
                           other organ ([T.sub.4],
                           [N.sub.0], [M.sub.0])

C          Stage III       Regional lymph nodes involved    30-40%
                           (any [T.sub.4], [N.sub.1]
                           [M.sub.0])

D          Stage IV        Distant metastasis (any T, any   <5%
                           N, [M.sub.1])

Table 4: Primary and secondary prevention strategies of CRC.
Primary

(i) Diet. A diet high in vegetables, fruits, dairy products,

olive oil, fish, and whole grains and low in red and processed
meats has been shown to lower CRC risk [21-23].

(ii) Physical Activity. Physically active individuals have 24%
lower risk of CRC development than those who have a
sedentary lifestyle.

Physical activity promotes the production of interleukin-6
(IL-6) and decreases the expression of inducible nitric oxide
synthase (iNOS) and tumor necrosis factor-alpha (TNF-[alpha])
in plasma and colon, leading to enhanced immunity [24, 25].
(iii) NSAIDs. They reduce the risk of CRC by blocking

cyclooxygenase (COX) enzymes, so inhibit prostaglandin
production, which are known to promote tumor
angiogenesis and cell proliferation [26].

Secondary

(i) Fecal Tests. Fecal occult blood test (FOBT) and fecal
immunochemical test (FIT) detect hidden blood in the stool,
while fecal DNA test detects DNA in the stool [27-29].

(ii) Flexible Sigmoidoscopy. It is performed using an endoscope
that allows the examination of the surface up to 60 cm from the
anal verge (rectum, sigmoid colon, and part of the descending
colon). It is done after colon lavage using enema or
administering laxatives without the need of sedation [30].

(iii) Colonoscopy. It is performed using an endoscope, which allows
an examination of the entire colon surface. It must be done
under intravenous sedation and requires being on a low-residue
diet, colon lavage using laxatives, and drinking plenty
of water the day before the test [31].

Table 5: Examples of some dietary components that decrease risk of
CRC.

Fiber        (i) A high-fiber diet has a protective effect from
             CRC as it decreases transit time through the
             gastrointestinal tract, dilutes colonic contents,
             and enhances bacterial fermentation. This can
             increase the production of short-chain fatty acids
             that interfere with numerous regulators of the
             cell cycle, proliferation, and apoptosis such as
             [beta]-catenin, p53, and caspase 3 genes [35, 36]

             (ii) Corn, beans, avocado, brown rice, lentils,
             pear, artichoke, carrots, oatmeal, broccoli, and
             apples are examples of diet rich in fiber [37]

Fish oil     (i) Fish oil rich in omega-3 fatty acids may
             inhibit the promotion and progression of cancer
             through suppression of arachidonic acid-derived
             eicosanoid biosynthesis, which results in altered
             immune response to cancer and modulation of
             inflammation, cell proliferation, apoptosis,
             metastasis, and angiogenesis [38]

             (ii) It also influences transcription factor
             activity, gene expression, and signal
             transduction, which leads to changes in
             metabolism, cell growth, and differentiation
             [38-40]

Olive oil    (i) Olive oil reduces deoxycholic acid in the
             human colon and rectum

             (ii) Deoxycholic acid was found to reduce diamine
             oxidase, a main enzyme for the metabolism of
             ingested histamine and control of mucosal
             proliferation in the ileal and the colonic mucosa
             [41]

Folate       (i) Folate acts as donors of methyl groups in the
             biosynthesis of nucleotide precursors used for
             DNA synthesis and methylation of DNA, RNA,
             and protein and participates in the maintenance
             of genomic stability [42, 43]

             (ii) Spinach, broccoli, strawberries, raspberries,
             beans, peas, lettuce, lentils, and celery are
             examples of diet rich in folate [37]

Calcium      (i) Calcium can suppress epithelial cell
             proliferation in the colon by binding to bile
             acids and ionized fatty acids [44]

             (ii) Calcium can act directly by reducing
             proliferation, stimulating differentiation, and
             inducing apoptosis via upregulation of p21 and
             Bcl-2 in the colonic mucosa [44-47]

Table 6: Methods of allelic discrimination used in SNP genotyping
[63].

Enzymatic       Enzymatic cleavage is based on the ability of
cleavage        certain classes of enzymes to cleave DNA by
                recognition of specific sequences and structures.
                Such enzymes can be used for discrimination
                between alleles when SNP sites are located in an
                enzyme recognition sequence and allelic
                differences affect recognition. For example,
                restriction fragment length polymorphism (RFLP) is
                based on genotyping a SNP located in a restriction
                enzyme site using PCR product containing the SNP
                that is incubated with corresponding restriction
                enzyme. The reaction product is run on a gel, and
                SNP genotype is easily determined from the product
                sizes [64].

Primer          In a typical primer extension reaction, a primer
extension       is designed to anneal with its 3\ end adjacent to
                a SNP site and extended with nucleotides by
                polymerase enzyme. The identity of the extended
                base is determined either by fluorescence or mass
                to reveal SNP genotype, for example, the PinPoint
                assay, MassEXTEND tm, SPC-SBE, and GOODassay
                primer extension-based methods, where SNP-specific
                primers are simultaneously extended with
                various nucleotides using PCR products as a
                template [65].

Hybridization   Hybridization approaches use differences in the
                thermal stability of double-stranded DNA to
                distinguish between perfectly matched and
                mismatched target-probe. For example, the TaqMan[R]
                genotyping assay combines hybridization and 5                nuclease activity of polymerase coupled with
                fluorescence detection. The allele-specific probes
                carry a fluorescent dye at one end (reporter) and
                a nonfluorescent dye at the other end (quencher).
                The intact probes show no fluorescence owing to
                the close proximity between the reporter and
                quencher dyes. During PCR primer extension, the
                enzyme only cleaves the hybridized probe that is
                perfectly matched, freeing the reporter dye from
                the quencher. The reporter dye generates a
                fluorescent signal, whereas the mismatched probe
                remains intact and shows no fluorescence [66].

Ligation        Ligation approach employs specificity of ligase
                enzymes. When two oligonucleotides hybridize to
                single-stranded template DNA with perfect
                complementarity, adjacent to each other, ligase
                enzymes join them to form a single
                oligonucleotide. Three oligonucleotide probes are
                used in traditional ligation assays, 2 of which
                are allele-specific and bind to the template at
                the SNP site. The third probe is common and binds
                to the template adjacent to the SNP immediately
                next to the allele-specific probe. For example,
                combinatorial fluorescence energy transfer tags
                are composed of fluorescent dyes that can transfer
                energy when they are in close proximity. Tags with
                different fluorescence signatures can be created
                using a limited number of dyes by varying the
                number of dyes used and spacing between the dyes
                [67].

Table 7: Some of the published GWASs on CRC (100).

Reference    Gene or region          Population          Sample size
 SNP (rs)                                                 for stage

rs4939827      18q21 SMAD7        First stage: UK         940 cases/
                                  Second stage: UK       965 controls

rs6983267         8q24            First stage: UK         930 cases/
                                  Second stage: UK       960 controls

rs10505477        8q24          First stage: Canada      1257 cases/
                                                        1336 controls
rs719725          9p24         Other stages: Canada,
                                  US, and Scotland

rs4779584      15q13 CRAC1        First stage: UK         730 cases/
                                  Second stage: UK       960 controls

rs4939827      18q21 SMAD7     First stage: Scotland

rs7014346         8q24           Second stage and         98 cases/
                               replication: Canada,     1002 controls
rs3802842         11q23         UK, Israel, Japan,
                                       and EU

rs4444235     14q22.2 BMP4        First stage: UK

rs9929218     16q22.1 CDH1                               6780 cases/
                                                        6843 controls
rs10411210     19q13 RHPN2       Replication: EU,
                                       Canada
rs961253         20p12.3

Reference     Sample size for     Genotyping platform      Study
 SNP (rs)    subsequent stages       (Nb. of SNPs)       reference

rs4939827       7473 cases/       Asymetrix (550,163)      (101)
               5984 controls

rs6983267       7334 cases/        Illumina (547,647)      (102)
               5246 controls

rs10505477      4024 cases/          Illumina and          (103)
               4042 controls      Affymetrix (99,632)
rs719725

rs4779584       4500 cases/        Illumina (547,647)      (104)
               3860 controls

rs4939827

rs7014346       16476 cases/       Illumina (541,628)      (105)
               15351 controls
rs3802842

rs4444235

rs9929218       13406 cases/       Multiple (38,710)       (106)
               14012 controls
rs10411210

rs961253

Table 8: Gene polymorphisms associated with CRC.

Gene                     Reference     Effect on CRC
                         SNP (rs)
                                       A promoter polymorphism due to
Matrix                   rs34016235    a C to T substitution results
metalloproteinases-9                   in the loss of the binding
(MMP 9)                                site of a nuclear protein to
                                       this region of the MMP 9 gene
                                       promoter. The polymorphism is
                                       associated with lymph node
                                       metastasis of CRC.

COX-2                    rs20417       The C allele has lower
                                       promoter activity than the G
                                       allele, and GG genotype in
                                       smokers is associated with a
                                       significant increase in the
                                       risk of CRC compared to
                                       nonsmokers.

Vitamin D receptor       rs1544410     Polymorphism of the vitamin D
                                       receptor gene to be associated
                                       with an increased risk of
                                       colon cancer.

Bone morphogenetic       rs4444235     The rs4444235 increases risk
protein 4 (BMP 4)                      of CRC development through its
                                       cis-acting regulatory
                                       influence on BMP4 expression.

Phospholipase A2         rs9657930     Polymorphisms in the
                                       phospholipase A2 gene is
                                       associated with the risk of
                                       the rectal cancer.

Colorectal adenoma       rs4779584     The rs4779584 polymorphism is
and carcinoma 1                        associated with increased risk
                                       of CRC among Caucasian not
                                       Asian populations.

Eukaryotic translation   rs16892766    The rs16892766 polymorphism is
initiation factor 3                    associated with increased risk
                                       of CRC but not adenoma among
                                       Caucasian.

Cadherin-1               rs9929218     The minor allele of rs9929218
                                       has reduced E-cadherin
                                       expression and resulted in
                                       worsening the survival of CRC
                                       patients.

                                       The rs2234767 contributes to
FAS                      rs2234767     an increased risk of CRC by
                                       altering recruitment of SP1/
                                       STAT1 complex to the FAS
                                       promoter for transcriptional
                                       activation.

Maternally               rs7158663     The rs7158663 changes the
expressed gene 3                       folding structures of
                                       maternally expressed gene 3;
                                       therefore, it contributes to
                                       genetic susceptibility of CRC.

Fc-g receptor gene       rs1801274     The rs1801274 changes the
                                       amino acid from histidine (H)
                                       to arginine. CRC patients with
                                       Fc/g receptor H/H genotype
                                       have better survival.

SPSB2 gene               rs11064437    The rs11064437 contributes to
                                       an increased risk of CRC by
                                       disrupting the splicing and
                                       introduction of a
                                       transcriptional isoform with a
                                       shortened untranslated region
                                       of SPSB2 gene.

TPP1                     rs149418249   Prevents TPP1-TIN2
                                       interaction, shortening the
                                       telomere length, and as a
                                       consequence, enhances cell
                                       proliferation

SLC22A5                  rs27437       The G allele decreases the
                                       expression of SLC22A5 via
                                       influencing the TF-binding
                                       upstream of the gene, leading
                                       to higher CRC risk.

KBTBD11                  rs11777210    C allele allows binding of
                                       MYC, a potent oncogene,
                                       preventing the expression of
                                       KBTBD11, a potent tumor
                                       suppressor.

miR-17-92                rs9588884     The G allele lowers the CRC
cluster                                risk by decreasing
                                       transcriptional activity and
                                       consequently lowering levels
                                       of miR-20a.

Gene                     Reference

Matrix                   [78]
metalloproteinases-9
(MMP 9)

COX-2
                         [79]

Vitamin D receptor       [80]

Bone morphogenetic       [81]
protein 4 (BMP 4)

Phospholipase A2         [82]

Colorectal adenoma       [83]
and carcinoma 1

Eukaryotic translation   [84]
initiation factor 3

Cadherin-1               [85]

FAS                      [86]

Maternally               [87]
expressed gene 3

Fc-g receptor gene       [88]

SPSB2 gene               [89]

TPP1                     [90]

SLC22A5                  [91]

KBTBD11                  [92]

miR-17-92                [93]
cluster

Table 9: The role of TGF-[beta] in various cell processes.

Cytostasis                (i) TGF-[beta] can activate cytostatic gene
                          responses at any point in the cell cycle
                          phases G1, S, or G2 [112]

                          (ii) TGF-[beta] induces activation of the
                          cyclin-dependent kinase (CDK) inhibitors
                          [113-115] and repression of the growth-
                          promoting transcription factors c-MYC and
                          inhibitors of differentiation (ID1, ID2, and
                          ID3) [116].

                          TGF-[beta] induces apoptosis through

                          (i) upregulation of SH2-domain-containing
Apoptosis                 inositol-5-phosphatase expression, which
                          inhibits signaling via the survival protein
                          kinase AKT [117]

                          (ii) induction of TGF-[beta]-inducible early-
                          response gene, which induces the generation
                          of ROS and the loss of the mitochondrial
                          membrane potential preceding the apoptotic
                          death [118, 119]

                          (iii) induction of death-associated protein
                          kinase [117]

                          For immune suppression, TGF-[beta] plays a
                          critical role through

Immunity                  (i) blocking antigen-presenting cells such as
                          dendritic cells, which acquire the ability to
                          effectively stimulate T cells during an
                          immune response [120]

                          (ii) decreasing the activity of natural
                          killer cells and neutrophils [121]

                          (i) TGF-[beta] induces the expression of
Angiogenesis              matrix metalloproteinases (MMPs) on both
                          endothelial cells and tumor cells, allowing
                          the release of the endothelial cells from the
                          basement membrane [122]

                          (ii) TGF-[beta] can also induce the
                          expression of angiogenic factors such as
                          vascular endothelial growth factor (VEGF) and
                          connective-tissue growth factor (CTGF) in
                          epithelial cells and fibroblasts [123, 124]

                          The migratory ability of epithelial cells
                          relies on loss of cell-cell contacts, a
                          process that is commonly referred to as the
                          EMT. It is marked by the loss of E-cadherin
                          and the expression of mesenchymal proteins
                          such as vimentin and N-cadherin [125].

Epithelial-mesenchymal    (i) TGF-[beta] was reported to destabilize
transition (EMT)          the E-cadherin adhesion complex resulting in
                          its loss in pancreatic cancer [126].
                          Alternatively, in epithelial cell lines, TGF-
                          [beta] can deacetylate the E-cadherin
                          promoter, thus repressing its transcription
                          [127]

                          (ii) TGF-[beta] was found to upregulate
                          vimentin in prostate cancer [128]

                          (iii) TGF-[beta] upregulates MMPs to promote
                          invasion through proteolytic degradation and
                          remodeling of the ECM [129]

Table 10: TGF-[beta]-induced non-Smad signaling pathways.

c-Jun N-terminal       (i) TGF-[beta] can rapidly activate JNK and
kinases (JNK)/p38      p38 through MAPK kinases (MKK4, MKK 3-6) in
activation             various cell lines [133,134]. Activation of
                       JNK-P38 plays a role in TGF-[beta]-induced
                       apoptosis and in TGF-[beta]-induced EMT
                       [135].

Extracellular          (i) TGF-[beta] was found to activate the
signal-regulated       mitogen-activated protein kinase (MAPK)-
kinase (ERK)           extracellular signal-regulated kinase (ERK)
activation             pathway which are important for TGF-[beta]
                       mediated EMT [125, 136].

Phosphoinositide       (i) TGF-[beta] was reported to rapidly
3-kinase (PI3-K)/      activate phosphoinositide 3-kinase (PI3-K) as
AKT activation         indicated by the phosphorylation of its
                       downstream effector Akt [137] (ii) Although
                       the PI3-K-Akt pathway is a non-Smad pathway
                       contributing to TGF-[beta]-induced EMT, it
                       can antagonize Smad-induced apoptosis and
                       growth inhibition [138]

Rho-like GTPases       (i) The Rho-like GTPases, such as Ras homolog
                       gene family, member A (RhoA) plays an
                       important role in controlling dynamic
                       cytoskeletal organization, cell motility, and
                       gene expression and is a key player in TGF-
                       [beta]-induced EMT [139]

                       (ii) TGF-[beta] regulates RhoA activity in
                       two different modes as it induces a rapid
                       activation of RhoA during the early phase of
                       stimulation and then downregulates the level
                       of RhoA protein at later stages, both of
                       these modes of regulation appear to be
                       essential for TGF-[beta]-induced EMT [140]

Table 11: Alterations of some components of TGF-# pathway in
human tumors.

TGF-[beta]R2           (i) The TGF-[beta]R2 gene has been mapped to
                       chromosome 3p, a chromosome in which mutation
                       was observed in small cell lung carcinoma
                       (SCLC), non-small-cell lung carcinoma
                       (NSCLC), CRCs, and ovarian and breast cancers
                       [142-144] (ii) Besides mutations in the
                       coding region of TGF-[beta]R2, loss of
                       expression of TGF-[beta]R2 in NSCLCs, bladder
                       cancer, and breast cancer were reported
                       [145-147]

TGF-[beta]R1           (i) The TGF-[beta]R1 gene has been mapped to
                       chromosome 9q (ii) Mutation in TGF-[beta]
                       gene was reported in ovarian cancer, head and
                       neck squamous cell carcinomas (HNSCC), and
                       breast cancer [148-150] (iii) Homozygous
                       deletion of TGF-[beta]R1 was also identified
                       in pancreatic and biliary adenocarcinomas
                       [151]

SMAD3                  (i) The gene for SMAD3 is located in
                       chromosome 15q21-q22 (ii) The rate of
                       mutation in the SMAD3 gene is rare, and there
                       are only few examples of such defects in
                       Smad3 expression that was found in some
                       gastric cancer and leukemia [152, 153]

SMAD2/SMAD4            (i) Chromosome 18q has genes encodes for
and SMAD7              SMAD2, SMAD4, and SMAD7 (ii) Mutation in
                       chromosome 18q was found in about 30% of
                       neuroblastoma, breast, prostate, and cervical
                       cancers and even more frequently in HNSCC
                       (40%), NSCLC (56%), colon cancer (60%),
                       gastric cancer (61%), and 90% of pancreatic
                       tumors [154, 155]

Table 12: Association studies of SNPs in SMAD7 gene and CRC.

Population          Reference    Location    Association    Reference
                     SNP (rs)
                                              In women:
African American    rs4939827    Intron 3        yes          [166]
and Caucasian       rs4464148    Intron 3        Yes
                    rs12953717   Intron 3        Yes
Caucasian           rs4939827    Intron 3        Yes          [167]
                    rs4464148    Intron 3         No
Swedish             rs4939827    Intron 3        Yes          [168]
European            rs4464148    Intron 3        Yes          [169]
                    rs4939827    Intron 3         No
                    rs4939827    Intron 3         No
Chinese             rs12953717   Intron 3        Yes          [170]
                    rs4464148    Intron 3         No
African American    rs4939827    Intron 3        Yes          [171]
Chinese             rs4939827    Intron 3        Yes           [76]
                                                CRC vs
                                             control: no
Romanian            rs4939827    Intron 3     Rectal vs       [172]
                                                colon
                                             cancer: yes
Caucasian           rs4939827    Intron 3        Yes          [173]
Croatian            rs4939827    Intron 3        Yes           [77]
Italian             rs4939827    Intron 3        Yes          [174]
Korean              rs4939827    Intron 3        Yes          [175]
Spanish             rs4939827    Intron 3        Yes          [176]
French              rs4939827    Intron 3        Yes          [177]
                    rs58920878   Intron 3        Yes

Table 13: Serum YKL-40 levels (ng/ml) in patients with
inflammation, tissue remodeling, or fibrosis [201].

Disease                     Median serum     Reference
                            YKL-40 (ng/l)
Viral hepatitis                   83
Noncirrhotic fibrosis            158           [202]
Posthepatitis cirrhosis          204
Rheumatoid arthritis             110           [203]
Streptococcus pneumoniae         342           [200]
  bacteremia
Osteoarthritis                   112           [204]
UC, severe                        59
CD, severe                        59           [205]
Pulmonary sarcoidosis            201           [206]
Asthma                            92           [207]

Table 14: Serum YKL-40 levels (ng/ml) in patients with localized or
advanced cancer [201].

Disease                       Median serum         Reference
                              YKL-40 (ng/l)
Metastatic breast cancer      80                   [209]
CRC                           160                  [210]
Glioblastoma multiforme       130                  [195]
Lower grade gliomas           101
Primary breast cancer         57                   [211]
Small cell lung cancer        82
Local disease                 71                   [192]
Extensive disease             101
Metastatic prostate cancer    112                  [208]
Ovarian cancer, all stages    94
Ovarian cancer, stage III     168                  [212]
Ovarian cancer, relapse       94

Table 15: Association of some CHI3L1 SNPs with diseases.

Disease                           Population       Reference
                                                    SNP (rs)

Sarcoidosis                       Caucasian        rs10399931
Schizophrenia                     Caucasian        rs10399805
Liver fibrosis                    Caucasian        rs4950928
Glioblastoma                      Caucasian        rs4950928
Asthma and atopy                    Danish         rs4950928
                                                   rs4950928
                                                   rs6691378
Rheumatoid arthritis                Danish         rs10399931
                                                    rs880633
Coronary heart disease             Chinese         rs10399931
Schizophrenia                      Japanese        rs4950928
Atrial fibrillation                 Danish         rs4950928
Asthma                        African Americans    rs4950928
Cervical cancer                   Taiwanese        rs10399805
                                                   rs4950928
                                                   rs10399931
Asthma                            Taiwanese        rs1538372
Atherosclerosis                   Taiwanese        rs10399931
Asthma                              Indian         rs4950928
Non-Hodgkin's lymphoma              Danish         rs4950928
Asthma                             Swedish         rs4950928
Venous thromboembolism              Danish         rs4950928
Coronary artery disease           Taiwanese        rs4950928

Disease                         Location      Association    Reference

Sarcoidosis                     Promoter           No          [226]
Schizophrenia                   Promoter          Yes          [163]
Liver fibrosis                  Promoter          Yes          [225]
Glioblastoma                    Promoter           No          [227]
Asthma and atopy                Promoter          Yes          [228]
                                Promoter           No
                                Promoter           No
Rheumatoid arthritis            Promoter           No          [229]
                                 Exon 5            No
Coronary heart disease          Promoter           No          [230]
Schizophrenia                   Promoter          Yes          [231]
Atrial fibrillation             Promoter           No          [232]
Asthma                          Promoter          Yes          [233]
Cervical cancer                 Promoter          Yes          [234]
                                Promoter           No
                                Promoter          Yes
Asthma                        Intron2/exon3       Yes          [235]
Atherosclerosis                 Promoter           No          [236]
Asthma                          Promoter           No          [237]
Non-Hodgkin's lymphoma          Promoter          Yes          [238]
Asthma                          Promoter           No          [239]
Venous thromboembolism          Promoter           No          [240]
Coronary artery disease         Promoter          Yes          [241]

Figure 1: Age-standardized CRC incidence rate
by sex and world area, GLOBOCAN 2012.

                              Males   Females

Australia/ New Zealand        44.8    32.2
Southern Europe               39.5    24.1
Western Europe                39.1    24.9
Northern Europe               36.5    25.3
Central and Eastern Europe    34.5    21.7
Northern America              30.1    22.7
Eastern Asia                  22.4    14.6
Micronesia/Polynesia          18.5    11.8
Western Asia                  17.6    12.4
South America                 17.1    14.6
Carribean                     16.3    16.6
South-Eastern Asia            15.2    10.2
Southern Africa               14.2    8.7
Melanesia                     11.1    6.9
Central America               8.8     7.1
Northern Africa               8.5     I6.9
Eastern Africa                7.1     6.1
South-Central Asia            7       5.2
Middle Africa                 4.7     4.8
Western Africa                4.5     3.8

Age-standardized rate per 100,000

Note: Table made with bar graph.
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Author:Fattah, Amal Ahmed Abd El-; Sadik, Nermin Abdel Hamid; Shaker, Olfat Gamil; Kamal, Amal Mohamed
Publication:Mediators of Inflammation
Date:Jan 1, 2018
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