Molecular Subtypes of Colorectal Cancer and Their Clinicopathologic Features, With an Emphasis on the Serrated Neoplasia Pathway.
THREE MOLECULAR CARCINOGENESIS PATHWAYS AND 2 MORPHOLOGIC MULTISTEP PATHWAYS
Colorectal cancer is a heterogeneous disease entity in terms of both molecular carcinogenesis and morphologic multistep pathways. Three molecular carcinogenesis pathways have been identified: (1) chromosomal instability (CIN), (2) microsatellite instability (MSI), and (3) CpG island methylator phenotype (CIMP) or epigenetic instability pathways. The 2 morphologic multistep pathways are the classical pathway (the so-called adenoma-carcinoma sequence) and the serrated neoplasia pathway. The CIN pathway is characterized by alterations in the number and structure of chromosomes and accompanying genetic mutations of proto-oncogenes and tumor suppressor genes. The MSI pathway features alterations in the number of nucleotide repeats located in the exons and subsequent frameshift mutations in tumor suppressor genes or tumor-related genes. The epigenetic instability (or CIMP) pathway is characterized by widespread hypermethylation of numerous promoter CpG island loci and consequent inactivation of tumor suppressor genes or tumor-related genes. The classical pathway (so-called adenoma-carcinoma sequence) begins with premalignant lesions comprising conventional adenomas, including tubular or tubulovillous adenomas, whereas the serrated neoplasia pathway begins with hyperplastic polyps or sessile or traditional serrated adenomas. These 2 morphologic pathways are driven by different molecular pathways: the classical pathway is driven by either CIN or MSI, whereas the serrated neoplasia pathway has epigenetic instability as its initial driving force and MSI as an optional secondary force. Although Lynch syndrome CRCs and sporadic MSI-high (MSI-H) CRCs both have a high level of MSI, their premalignant lesions are different because they develop through different morphologic multistep pathways: Lynch syndrome tumors follow the classical pathway and manifest their premalignant lesions as tubular or tubulovillous adenoma, (14, 15) whereas the premalignant lesions of sporadic MSI-H CRCs are sessile serrated adenomas that arise through the serrated neoplasia pathway and undergo further hypermethylation-associated inactivation of MLH1 and subsequent acquisition of high level MSI. (16) The Cancer Genome Atlas study results demonstrate that the CIN and MSI pathways are mutually exclusive. (17) Whereas the CIMP pathway overlaps with the MSI pathway because of the presence of sporadic MSI-H CRCs, which are also usually CIMP-high (CIMP-H), the CIMP pathway does not appear to be in an exclusive relationship with the CIN pathway. CIMP-H/ non-MSI-H CRCs show some copy number variations across the genome, although the degree of CIN is less pronounced than that of CIMP-negative or -low (CIMP-0,L)/non-MSI-H CRCs. (18) This finding suggests that the CIMP pathway itself may not be sufficient for the malignant transformation of serrated polyps and requires collaboration with either the CIN or MSI pathway to promote successful malignant transformation.
GEOGRAPHY-, AGE-, AND SEX-DEPENDENT DIFFERENCES IN THE PROPORTIONS OF MOLECULAR CARCINOGENESIS PATHWAYS
The frequency of MSI in CRCs differs between Western and Eastern populations. MSI-H CRCs comprise approximately 15% of all CRCs in the United States but less than 10% of all CRCs in South Korea or Taiwan. (19-26) Because the prevalence of Lynch syndrome is approximately 3% and is similar in Eastern and Western patients with CRC, (27-30) sporadic MSI-H CRCs account for the difference in the proportion of MSI-H CRCs in all CRCs between populations in South Korea and the United States. Most sporadic MSI-H CRCs develop from sessile serrated adenomas through CIMP-associated inactivation of MLH1. The reason why the proportion of sporadic MSI-H CRCs is lower in South Korea is because the proportion of CIMP-H CRCs is lower in all CRCs in South Korea than in all CRCs in the United States. (31, 32) The proportion of CIMP-H CRCs defined by at least 5 of 8 methylated CIMP panel markers is lower in South Korea than in the United States (6%-7% versus 17-18%, respectively). (21, 31, 33, 34) Accordingly, the mutation rate of BRAF is lower in CRCs in the Korean population than in CRCs in the American population (4%-5% versus 13%-15%, respectively). (26, 31, 35-38) Most Chinese studies have reported a relatively low frequency of BRAF mutation in CRCs (< 7%). (39) Within the same geographic area, white individuals have a higher rate of CIMP-H in CRCs than do African American or Asian American individuals (14%-18% versus 8%-11% versus 7%, respectively). (35, 40) Thus, the lower rate of MSI-H in African American than in white individuals reported in a population-based study (14% versus 7%, respectively) might be attributed to the lower rate of CIMP-H in African American than in white persons. (40, 41)
An association between MSI-H CRCs and female sex has been recognized but the association is valid only when MSIH CRCs are sporadic. In Lynch syndrome, CRC risk is higher in male mutation carriers than in female mutation carriers. (42) In other words, an association between MSI-H CRCs and female sex is provided by CIMP-H because MSIH CRCs are generated by CIMP-associated inactivation of MLH1, and CIMP-H is closely associated with female sex. The relationship between female sex and CIMP-H is persistent regardless of geographic location, race, or age. (40, 43-45) Although CIMP-H is associated with increased patient age, (43, 46, 47) the proportion of CIMP-H is higher in females than in males regardless of age. (45)
MOLECULAR SUBTYPES BASED ON COMBINED CIMP AND MSI STATUSES
Jass (15) classified CRCs into 5 molecular subtypes primarily by underlying types of genetic instability and the presence of DNA methylation: (1) CIMP-H/MSI-H, (2) CIMP-H/non-MSI-H, (3) CIMP-L/non-MSI-H, (4) CIMP-0/non-MSI-H, and (5) CIMP-0/MSI-H. Jass' subtypes 1 and 2 and subtype 4 reflect CRCs arising from the serrated neoplasia pathway and the classical pathway, respectively. Jass' subtype 5 was suggested to be indicative of possible Lynch syndrome. However, with regard to Jass' subtype 3, it is unclear whether CRCs arise from the classical pathway or the serrated neoplasia pathway. Furthermore, there are no consensus diagnostic criteria for CIMP-L. Conceptually, the term CpG island methylator phenotype-L (CIMP-L) was coined to describe a group of tumors that show intermediate amounts of aberrant DNA methylation. (48) CIMP-L is defined when the number of methylated CIMP panel markers exceeds 0 but does not reach the cutoff value for CIMP-H. In the 8-marker panel, CIMP-L tumors have methylation at 1 to 4 or 5 markers, whereas in the 5-marker panel, CIMP-L has methylation at 1 to 2 or 3 markers. (45, 48) Because conventional adenomas or CRCs contiguous with conventional adenomas often harbor methylation of 1 or more of the 8-panel markers or of 1 or 2 of the 5-panel markers, (49) CIMP-L/non-MSI-H CRCs are thought to arise from the classical pathway as well as the serrated neoplasia pathway. (15) Thus, the clinicopathologic and molecular features overlap substantially between subtypes 3 and 4. (15)
CLINICOPATHOLOGIC OR MOLECULAR FEATURES OF 4 MOLECULAR SUBTYPES OF CRCS
In our previous study, (31) we analyzed the CIMP and MSI statuses of surgically resected CRCs (n = 734). Of the 5 molecular subtypes according to Jass' classification, the CIMP-0/non-MSI-H subtype was the most common, comprising 63% (n = 464) of the CRCs, whereas the CIMP-H/MSI-H subtype was the least common, comprising 3% (n = 19) of the CRCs (Table 1). The age of onset was the highest for the CIMP-H/MSI-H subtype and the lowest for the CIMP-0,L/MSI-H subtype. The 5 molecular subtypes showed distinct clinicopathologic and molecular features. Compared with the CIMP-0/non-MSI-H subtype, which is the most common subtype, the CIMP-H/non-MSI-H subtype was associated with a more common right-sided colon location, poor differentiation, luminal serration, nodal metastasis, distant metastasis, and BRAF mutation. Compared with the other 3 molecular subtypes, the CIMP-0,L/ MSI-H subtype was associated with the youngest age of onset, less frequent nodal metastasis, less frequent distant metastasis, and near absence of BRAF mutation.
Regardless of CIMP status, the 2 MSI-H subtypes showed a more frequent right-sided colon location, less frequent dirty necrosis, more frequent Crohn-like lymphoid reaction, more frequent mucinous histology, and less frequent KRAS mutation than the CIMP-0,L/non-MSI-H subtype. Despite these shared clinicopathologic and molecular features, the CIMP-H/MSI-H and CIMP-0,L/MSI-H subtypes differ in several clinicopathologic features, including age of onset, tumor multiplicity in the large bowel, cancer stage, and frequency of BRAF mutation. These differences were corroborated in a large-scale study of MSI-H CRCs. (50) Although extensive exonal microsatellite alterations and increased point mutations caused by mismatch repair defects bestow very considerable overlap on the altered gene expression signatures between the 2 MSI-H subtypes, the serrated neoplasia pathway-associated gene signature can be found in the CIMP-H/MSI-H subtype. (51) Because serrated polyps, including hyperplastic polyps, sessile serrated adenomas, and traditional serrated adenomas, are associated with aberrant gastric-type differentiation, the CIMP-H/MSI-H subtype is characterized by a gain of gastric differentiation (ANXA10, TFF2, and MUC5AC expression) and loss of intestinal expression (CDX2 and KRT20 loss). (51, 52) Furthermore, histologic features that differ between the 2 MSI-H subtypes include sheeting appearance, eosinophilic cytoplasm, acinar appearance, signet ring cell formation, and stratified nuclei. The first 4 of these features are more frequent in the CIMP-H/MSI-H subtype, whereas the last feature is more frequent in the CIMP-0,L/MSI-H subtype. (50)
BOWEL SUBSITE DISTRIBUTION OF MOLECULAR SUBTYPES OF CRCS
Right-sided and left-sided colon cancers and rectal cancers differ in various clinicopathologic and molecular features. These differential clinicopathologic and molecular features do not change abruptly at the borders between the right-sided colon and the left-sided colon or between the left-sided colon and the rectum, but change gradually along the large bowel. (34) Yamauchi et al (34, 53) examined the clinicopathologic and molecular features of CRCs at 9 bowel subsites from the rectum to the cecum and found that the frequencies of female sex, poor differentiation, mucinous histology, CIMP-H, MSI-H, and BRAF mutation increased linearly along the bowel from the rectum to the ascending colon. Our previous study (31) also found a linear trend toward increasing female occurrence, advanced T category, N category, overall stage, poor differentiation, absence of luminal necrosis, luminal serration, mucinous histology, Crohn-like lymphoid reaction, CIMP-H, and MSI-H from the rectum to the cecum. These findings support the concept of the large bowel as a continuum rather than as 2 or 3 large-bowel subsections in terms of molecular and clinico-pathologic features.
The Figure illustrates the proportions of the 5 molecular subtypes in each bowel subsite from the cecum to the rectum. (31) For the cecum or ascending colon, the CIMP-0/ non-MSI-H subtype comprises approximately 50% of tumors, whereas this molecular subtype constitutes approximately 70% of the tumors in the sigmoid and rectosigmoid colon and the rectum, which may account for the observed differences in clinicopathologic features between right-sided cancers and left-sided or rectal cancers.
PROGNOSTIC IMPLICATIONS OF MOLECULAR SUBTYPES OF CRCS
The association between molecular subtypes and survival of colon cancers or CRCs was first explored by Ward et al (54) who showed that, of the 4 molecular subtypes generated by combinations of CIMP (CIMP-H versus CIMP-L,0) and MSI (MSI-H versus non-MSI-H) statuses, the CIMP-H/non-MSI-H subtype was associated with the shortest overall survival and disease-free survival time (Table 2). Ward et al (54) analyzed the CIMP panel markers CDKN2A (p16), MINT1, MINT2, MINT12, and MINT31 for their methylation statuses by using bisulfite or methylation-specific polymerase chain reaction in study subjects who included adjuvant-treated or untreated patients with stage I to IV CRC. Our previous studies, which analyzed stage I to IV CRC cases with or without adjuvant treatment, also found that the CIMP-H/non-MSI-H subtype was associated with the shortest overall survival time. (43, 55) In contrast, in a study by Ogino et al, (56) the CIMP-0,L/non-MSI-H subtype showed the worst cancer-specific survival in the cohort of study patients with stage I to IV colon cancer. A recent study (57) assessed the association between molecular subtypes and survival of patients with stage III colon cancer who were randomly assigned to treatment with adjuvant fluorouracil and leucovorin (FU/LV) alone or with irinotecan (IFL) (a phase III intergroup trial [C89803]) and found that the CIMP-H/non-MSI-H subtype was associated with the worst overall survival or disease-free survival in patients treated with adjuvant FU/LV but not in patients treated with adjuvant IFL. (57) In adjuvant IFL-treated patients, no survival difference was identified among the 4 molecular subtypes. This finding suggests that differences in the response to adjuvant therapies contribute to subtype-specific survival differences. In a study of patients with stage III or high-risk stage II CRC who were treated with adjuvant FU/LV plus oxaliplatin (FOLFOX), the 4 molecular subtypes did not show significant differences in disease-free survival. (58) In lieu of the CIMP-H/non-MSI-H subtype, concurrent methylation of 2 CIMP panel markers, CDKN2A (p16) and NEUROG1, was associated with recurrence after adjuvant FOLFOX treatment in stage II/III CRCs. In a recent population-based study that evaluated differences in survival across CRC subtypes defined by CIMP, MSI, BRAF mutation, and KRAS mutation status at stages I to IV, Phipps et al (35) suggested that the CIMP-H/non-MSI-H subtype with BRAF mutation had the highest disease-specific mortality. However, this study was not stratified according to the difference in adjuvant therapy regimens. Additional studies are needed to test whether the CIMP-H/non-MSI-H subtype with BRAF mutation has the highest diseases-pecific mortality in adjuvant FOLFOX-treated patients with stage II or III CRC. In a recent study of a large number of patients with stage III colon cancer who were treated with adjuvant FOLFOX or adjuvant FOLFOX plus cetuximab, Sinicrope et al (59) reported that non-MSI-H colon cancers with KRAS mutations or BRAF mutations were associated with poorer disease-free survival than non-MSI-H colon cancers with wild-type KRAS and BRAF. Additionally, MSIH colon cancers did not differ from non-MSI-H colon cancers with wild-type KRAS and BRAF in terms of disease-free survival. Overall, the findings suggest that the CIMP-H/ non-MSI-H subtype is associated with the shortest survival time in adjuvant FU-treated patients with stage III CRC but not in adjuvant IFL- or FOLFOX-treated patients with stage III CRC. In adjuvant FOLFOX-treated patients with stage III CRC, non-MSI-H CRCs with mutations in either KRAS or BRAF appear to have the worst outcomes.
SERRATED PATHWAY ADENOCARCINOMAS
The associations of reduced survival with (1) the CIMP-H/ non-MSI-H subtype in patients with CRC who are treated with FU-based adjuvant therapy and (2) non-MSI-H CRCs with BRAF or KRAS mutations in patients with CRC who are treated with adjuvant FOLFOX suggest that CRCs arising from the serrated neoplasia pathway may be more aggressive or more resistant to adjuvant therapy than those arising from the classical adenoma-carcinoma pathway. Serrated pathway adenocarcinomas refer to CRCs resulting from the serrated neoplasia pathway. Serrated adenocarcinoma is a newly introduced disease entity that defines a subset of colorectal adenocarcinomas characterized by epithelial serrations, eosinophilic or clear cytoplasm, abundant cytoplasm, vesicular nuclei, distinct nucleoli, absence of necrosis, extracellular mucin production, and cell balls and papillary fronds in mucinous areas. (60, 61) Given that 20% to 30% of CRCs are attributed to the serrated neoplasia pathway (32, 61) and that 7% to 12% of CRCs are serrated adenocarcinomas, (62-64) approximately one-third to one-half of serrated pathway adenocarcinomas are serrated adenocarcinomas. However, there has been no study examining the CIMP status of serrated adenocarcinomas. Thus, little is known regarding the proportions of CIMP-L and CIMP-H in serrated adenocarcinomas and regarding the proportion of serrated adenocarcinomas in CIMP-H CRCs. In other words, whether all CIMP-H CRCs show histologic features of serrated adenocarcinomas remains to be determined. Because conventional adenomas can harbor aberrant hypermethylation of CIMP panel markers, (49) CIMP-L CRCs can arise from either the serrated neoplasia pathway or the classical pathway. At present, methylation assays of CIMP panel markers cannot differentiate between CIMP-L serrated pathway adenocarcinomas and CIMP-L CRCs arising from the classical pathway. There is a need to develop auxiliary markers to identify serrated pathway adenocarcinomas. Immunohistochemical markers associated with the serrated neoplasia pathway include ANXA10, CLDN18, CTSE, MUC5AC, MUC6, TFF2, and VSIG2, which are overexpressed in hyperplastic polyps, sessile serrated adenoma/polyps, and traditional serrated adenomas, compared with conventional adenomas. (51, 52, 65-67) Little information is available regarding the expression statuses of these markers in CIMP-L CRCs and the differential clinicopathologic features of CIMP-L CRCs associated with the expression of these markers.
In summary, although the factors triggering the CIMP pathway are unknown, the CIMP pathway is associated with the right-sided colon, female sex, older age, and white patients. Familiarity with the differential clinicopathologic features of CRCs associated with molecular carcinogenesis pathways is a requisite for a better understanding of the mechanisms that lead CRCs to exhibit bowel subsite-associated differences with regard to age of onset, sex, race, and geographic area. Different responses of the molecular subtypes of CRCs to adjuvant therapy underlie the survival differences between sexes or between right-sided colon cancers and left-sided colon or rectal cancers. Clinical trials of adjuvant chemotherapies or targeted therapies should be conducted taking into account the molecular subtypes of CRCs. It is recognized that a considerable portion of serrated pathway adenocarcinomas do not exhibit any of CIMP-H, serrated adenocarcinoma histology, or direct contiguity with serrated polyps but instead show CIMP-L. Because CIMP-L CRCs can arise from both the classical pathway and the serrated neoplasia pathway, it is necessary to develop molecular or immunohistochemical markers to identify CIMP-L serrated pathway adenocarcinomas. With the help of these biomarkers, a better understanding of the clinicopathologic and molecular features of CIMP-L serrated pathway adenocarcinomas will be reached.
This study was supported by a grant from the Basic Science Research Program through the National Research Foundation (NRF) funded by the Korean Ministry of Education (2013R1A1A2059080), an NRF grant funded by the Korean Ministry of Science, ICT and Future Planning (2011-0030049), a grant (2009-0093820) from the Priority Research Centers Program of the NRF, and a grant from the Korea Health Technology R&D Project of the Korea Health Industry Development Institute funded by the Korean Ministry of Health and Welfare (HI14C1277).
(1.) Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014; 64(1):9-29.
(2.) Cheng L, Eng C, Nieman LZ, Kapadia AS, Du XL. Trends in colorectal cancer incidence by anatomic site and disease stage in the United States from 1976 to 2005. Am J Clin Oncol. 2011; 34(6):573-580.
(3.) Siegel R, Desantis C, Jemal A. Colorectal cancer statistics, 2014. CA Cancer J Clin. 2014; 64(2):104-117.
(4.) Center MM, Jemal A, Smith RA, Ward E. Worldwide variations in colorectal cancer. CA Cancer J Clin. 2009; 59(6):366-378.
(5.) Sung JJ, Lau JY, Goh KL, Leung WK. Increasing incidence of colorectal cancer in Asia: implications for screening. Lancet Oncol. 2005; 6(11):871-876.
(6.) Shin A, Kim KZ, Jung KW, et al. Increasing trend of colorectal cancer incidence in Korea, 1999-2009. Cancer Res Treat. 2012; 44(4):219-226.
(7.) Abotchie PN, Vernon SW, Du XL. Gender differences in colorectal cancer incidence in the United States, 1975-2006. J Womens Health (Larchmt). 2012; 21(4):393-400.
(8.) Gonzalez EC, Roetzheim RG, Ferrante JM, Campbell R. Predictors of proximal vs. distal colorectal cancers. Dis Colon Rectum. 2001; 44(2):251-258.
(9.) Toyoda Y, Nakayama T, Ito Y, Ioka A, Tsukuma H. Trends in colorectal cancer incidence by subsite in Osaka, Japan. Jpn J Clin Oncol. 2009; 39(3):189-191.
(10.) Seydaoglu G, Ozer B, Arpaci N, Parsak CK, Eray IC. Trends in colorectal cancer by subsite, age, and gender over a 15-year period in Adana, Turkey: 1993-2008. Turk J Gastroenterol. 2013; 24(6):521-531.
(11.) Ollberding NJ, Nomura AM, Wilkens LR, Henderson BE, Kolonel LN. Racial/ethnic differences in colorectal cancer risk: the multiethnic cohort study. Intl Cancer. 2011; 129(8):1899-1906.
(12.) Inciardi JF, Lee JG, Stijnen T. Incidence trends for colorectal cancer in California: implications for current screening practices. Am J Med. 2000; 109(4): 277-281.
(13.) Rim SH, Seeff L, Ahmed F, King JB, Coughlin SS. Colorectal cancer incidence in the United States, 1999-2004: an updated analysis of data from the National Program of Cancer Registries and the Surveillance, Epidemiology, and End Results Program. Cancer. 2009; 115(9):1967-1976.
(14.) Walsh MD, Buchanan DD, Pearson SA, et al. Immunohistochemical testing of conventional adenomas for loss of expression of mismatch repair proteins in Lynch syndrome mutation carriers: a case series from the Australasian site of the colon cancer family registry. Mod Pathol. 2012; 25(5):722-730.
(15.) Jass JR. Classification of colorectal cancer based on correlation of clinical, morphological and molecular features. Histopathology. 2007; 50(1):113-130.
(16.) Goldstein NS. Small colonic microsatellite unstable adenocarcinomas and high-grade epithelial dysplasias in sessile serrated adenoma polypectomy specimens: a study of eight cases. Am J Clin Pathol. 2006; 125(1):132-145.
(17.) Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012; 487(7407):330-337.
(18.) Mo Q, Wang S, Seshan VE, et al. Pattern discovery and cancer gene identification in integrated cancer genomic data. Proc Natl Acad Sci USA. 2013; 110(11):4245-4250.
(19.) Kim YH, Min BH, Choi HK, et al. Sporadic colorectal carcinomas with low-level microsatellite instability in Korea: do they form a distinct subgroup with distinguished clinicopathological features? J Surg Oncol. 2009; 99(6):351-355.
(20.) Xiao H, Yoon YS, Hong SM, et al. Poorly differentiated colorectal cancers: correlation of microsatellite instability with clinicopathologic features and survival. Am J Clin Pathol. 2013; 140(3):341-347.
(21.) Bae JM, Lee TH, Cho NY, Kim TY, Kang GH. Loss of CDX2 expression is associated with poor prognosis in colorectal cancer patients. World J Gastroenterol. 2015; 21(5):1457-1467.
(22.) Boland CR, Goel A. Microsatellite instability in colorectal cancer. Gastroenterology. 2010; 138(6):2073-2087.e3.
(23.) Hong SP, Min BS, Kim TI, et al. The differential impact of microsatellite instability as a marker of prognosis and tumour response between colon cancer and rectal cancer. Eur J Cancer. 2012; 48(8):1235-1243.
(24.) Lin CC, Lai YL, Lin TC, et al. Clinicopathologic features and prognostic analysis of MSI-high colon cancer. Int J Colorectal Dis. 2012; 27(3):277-286.
(25.) Liang JT, Huang KC, Cheng AL, Jeng YM, Wu MS, Wang SM. Clinicopathological and molecular biological features of colorectal cancer in patients less than 40 years of age. Br J Surg. 2003; 90(2):205-214.
(26.) Lochhead P, Kuchiba A, Imamura Y, et al. Microsatellite instability and BRAF mutation testing in colorectal cancer prognostication. J Natl Cancer Inst. 2013; 105(15):1151-1156.
(27.) Lynch HT, de la Chapelle A. Hereditary colorectal cancer. N Engl J Med. 2003; 348(10):919-932.
(28.) Zhang YZ, Sheng JQ, Li SR, Zhang H. Clinical phenotype and prevalence of hereditary nonpolyposis colorectal cancer syndrome in Chinese population. World J Gastroenterol. 2005; 11(10):1481-1488.
(29.) Fujita S, Moriya Y, Sugihara K, Akasu T, Ushio K. Prognosis of hereditary nonpolyposis colorectal cancer (HNPCC) and the role of Japanese criteria for HNPCC. Jpn J Clin Oncol. 1996; 26(5):351-355.
(30.) Hampel H, Frankel WL, Martin E, et al. Feasibility of screening for Lynch syndrome among patients with colorectal cancer. J Clin Oncol. 2008; 26(35): 5783-5788.
(31.) Bae JM, Kim JH, Cho NY, Kim TY, Kang GH. Prognostic implication of the CpG island methylator phenotype in colorectal cancers depends on tumour location. Br J Cancer. 2013; 109(4):1004-1012.
(32.) Ogino S, Goel A. Molecular classification and correlates in colorectal cancer. J Mol Diagn. 2008; 10(1):13-27.
(33.) Ogino S, Kawasaki T, Kirkner GJ, Kraft P, Loda M, Fuchs CS. Evaluation of markers for CpG island methylator phenotype (CIMP) in colorectal cancer by a large population-based sample. J Mol Diagn. 2007; 9(3):305-314.
(34.) Yamauchi M, Morikawa T, Kuchiba A, et al. Assessment of colorectal cancer molecular features along bowel subsites challenges the conception of distinct dichotomy of proximal versus distal colorectum. Gut. 2012; 61(6):847-854.
(35.) Phipps AI, Limburg PJ, Baron JA, et al. Association between molecular subtypes of colorectal cancer and patient survival. Gastroenterology. 2015; 148(1):77-87.e2.
(36.) Park JH, Han SW, Oh DY, et al. Analysis of KRAS, BRAF, PTEN, IGF1R, EGFR intron 1 CA status in both primary tumors and paired metastases in determining benefit from cetuximab therapy in colon cancer. Cancer Chemother Pharmacol. 2011; 68(4):1045-1055.
(37.) Kwon MJ, Lee SE, Kang SY, Choi YL. Frequency of KRAS, BRAF, and PIK3CA mutations in advanced colorectal cancers: comparison of peptide nucleic acid-mediated PCR clamping and direct sequencing in formalin-fixed, paraffin-embedded tissue. Pathol Res Pract. 2011; 207(12):762-768.
(38.) Hanna MC, Go C, Roden C, et al. Colorectal cancers from distinct ancestral populations show variations in BRAF mutation frequency. PLoS One. 2013; 8(9):e74950.
(39.) Li L, Ma BB. Colorectal cancer in Chinese patients: current and emerging treatment options. Onco Targets Ther. 2014; 7:1817-1828.
(40.) Slattery ML, Curtin K, Sweeney C, et al. Diet and lifestyle factor associations with CpG island methylator phenotype and BRAF mutations in colon cancer. Int J Cancer. 2007; 120(3):656-663.
(41.) Carethers JM, Murali B, Yang B, et al. Influence of race on microsatellite instability and CD8+ T cell infiltration in colon cancer. PLoS One. 2014; 9(6): e100461.
(42.) Vasen HF, Stormorken A, Menko FH, et al. MSH2 mutation carriers are at higher risk of cancer than MLH1 mutation carriers: a study of hereditary nonpolyposis colorectal cancer families. J Clin Oncol. 2001; 19(20):4074-4080.
(43.) Nosho K, Irahara N, Shima K, et al. Comprehensive biostatistical analysis of CpG island methylator phenotype in colorectal cancer using a large population-based sample. PLoS One. 2008; 3(11):e3698.
(44.) Kim JH, Shin SH, Kwon HJ, Cho NY, Kang GH. Prognostic implications of CpG island hypermethylator phenotype in colorectal cancers. Virchows Arch. 2009; 455(6):485-494.
(45.) Weisenberger DJ, Siegmund KD, Campan M, et al. CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat Genet. 2006; 38(7):787-793.
(46.) Yagi K, Akagi K, Hayashi H, et al. Three DNA methylation epigenotypes in human colorectal cancer. Clin Cancer Res. 2010; 16(1):21-33.
(47.) Ahn JB, Chung WB, Maeda O, et al. DNA methylation predicts recurrence from resected stage III proximal colon cancer. Cancer. 2011; 117(9):1847-1854.
(48.) Ogino S, Kawasaki T, Kirkner GJ, Loda M, Fuchs CS. CpG island methylator phenotype-low (CIMP-low) in colorectal cancer: possible associations with male sex and KRAS mutations. J Mol Diagn. 2006; 8(5):582-588.
(49.) Kwon HJ, Kim JH, Bae JM, Cho NY, Kim TY, Kang GH. DNA methylation changes in ex-adenoma carcinoma of the large intestine. Virchows Arch. 2010; 457(4):433-441.
(50.) Bae JM, Kim MJ, Kim JH, et al. Differential clinicopathological features in microsatellite instability-positive colorectal cancers depending on CIMP status. Virchows Arch. 2011; 459(1):55-63.
(51.) Kim JH, Kim KJ, Rhee YY, et al. Gastric-type expression signature in serrated pathway-associated colorectal tumors. Hum Pathol. 2015; 46(5):643-656.
(52.) Kim JH, Rhee YY, Kim KJ, Cho NY, Lee HS, Kang GH. Annexin A10 expression correlates with serrated pathway features in colorectal carcinoma with microsatellite instability. APMIS. 2014; 122(12):1187-1195.
(53.) Yamauchi M, Lochhead P, Morikawa T, et al. Colorectal cancer: a tale of two sides or a continuum? Gut. 2012; 61(6):794-797.
(54.) Ward RL, Cheong K, Ku SL, Meagher A, O'Connor T, Hawkins NJ. Adverse prognostic effect of methylation in colorectal cancer is reversed by microsatellite instability. I Clin Oncol. 2003; 21(20):3729-3736.
(55.) Lee S, Cho NY, Choi M, Yoo EJ, Kim JH, Kang GH. Clinicopathological features of CpG island methylator phenotype-positive colorectal cancer and its adverse prognosis in relation to KRAS/BRAf mutation. Pathol Int. 2008; 58(2): 104-113.
(56.) Ogino S, Nosho K, Kirkner GJ, et al. CpG island methylator phenotype, microsatellite instability, BRAF mutation and clinical outcome in colon cancer. Gut. 2009; 58(1):90-96.
(57.) Shiovitz S, Bertagnolli MM, Renfro LA, et al. CpG island methylator phenotype is associated with response to adjuvant irinotecan-based therapy for stage III colon cancer. Gastroenterology. 2014; 147(3):637-645.
(58.) Han SW, Lee HJ, Bae JM, et al. Methylation and microsatellite status and recurrence following adjuvant FOLFOX in colorectal cancer. Int J Cancer. 2013; 132(9):2209-2216.
(59.) Sinicrope FA, Shi Q, Smyrk TC, et al. Molecular markers identify subtypes of stage III colon cancer associated with patient outcomes. Gastroenterology. 2015; 148(1):88-99.
(60.) Torlakovic E, Skovlund E, Snover DC, Torlakovic G, Nesland JM. Morphologic reappraisal of serrated colorectal polyps. Am J Surg Pathol. 2003; 27(1):65-81.
(61.) Bettington M, Walker N, Clouston A, Brown I, Leggett B, Whitehall V. The serrated pathway to colorectal carcinoma: current concepts and challenges. Histopathology. 2013; 62(3):367-386.
(62.) Makinen MJ, George SM, Jernvall P, Makela J, Vihko P, Karttunen TJ. Colorectal carcinoma associated with serrated adenoma--prevalence, histological features, and prognosis. J Pathol. 2001; 193(3):286-294.
(63.) Tuppurainen K, Makinen JM, Junttila O, et al. Morphology and microsatellite instability in sporadic serrated and non-serrated colorectal cancer. J Pathol. 2005; 207(3):285-294.
(64.) Garcia-Solano J, Perez-Guillermo M, Conesa-Zamora P, et al. Clinicopathologic study of 85 colorectal serrated adenocarcinomas: further insights into the full recognition of a new subset of colorectal carcinoma. Hum Pathol. 2010; 41(10):1359-1368.
(65.) Sentani K, Sakamoto N, Shimamoto F, Anami K, Oue N, Yasui W. Expression of olfactomedin 4 and claudin-18 in serrated neoplasia of the colorectum: a characteristic pattern is associated with sessile serrated lesion. Histopathology. 2013; 62(7):1018-1027.
(66.) Gonzalo DH, Lai KK, Shadrach B, et al. Gene expression profiling of serrated polyps identifies annexin A10 as a marker of a sessile serrated adenoma/ polyp. J Pathol. 2013; 230(4):420-429.
(67.) Delker DA, McGettigan BM, Kanth P, et al. RNA sequencing of sessile serrated colon polyps identifies differentially expressed genes and immunohistochemical markers. PLoS One. 2014; 9(2):e88367.
(68.) Sanchez JA, Krumroy L, Plummer S, et al. Genetic and epigenetic classifications define clinical phenotypes and determine patient outcomes in colorectal cancer. Br I Surg. 2009; 96(10):1196-1204.
(69.) Dahlin AM, Palmqvist R, Henriksson ML, et al. The role of the CpG island methylator phenotype in colorectal cancer prognosis depends on microsatellite instability screening status. Clin Cancer Res. 2010; 16(6):1845-1855.
Jeong Mo Bae, MD; Jung Ho Kim, MD, PhD; Gyeong Hoon Kang, MD, PhD
Accepted for publication September 28, 2015.
From the Department of Pathology, Seoul National University College of Medicine, Seoul, Korea.
The authors have no relevant financial interest in the products or companies described in this article.
Presented at the 14th Spring Seminar of the Korean Pathologists Association of North America (KOPANA); March 19-21, 2015; Boston, Massachusetts.
Reprints: Gyeong Hoon Kang, MD, PhD, Department of Pathology, Seoul National University College of Medicine, 110-799, Seoul, Korea (email: email@example.com).
Caption: Distribution of 5 molecular subtypes along bowel subsites. Abbreviations: CIMP-H, CpG island methylator phenotype-high; CIMP-L, CpG island methylator phenotype-low; CIMP-0, CpG island methylator phenotypenegative; MSI-H, high level of microsatellite instability.
Please Note: Illustration(s) are not available due to copyright restrictions.
Table 1. Clinicopathologic and Molecular Features of 4 Molecular Subtypes of Colorectal Cancers Based on Combinatory Statuses of CIMP and Microsatellite Instability (MSI) (a) CIMP-0/ CIMP-L/ Non-MSI-H, Non-MSI-H, No. (%) No. (%) (n = 464, 63%) (n = 174, 24%) Age, average, y 61.4 61.1 Female 179 (39) 66 (38) Right-sided colon location 99 (21) 44 (25) Stage III or IV 241 (52) 89 (51) Distant metastasis 81 (18) 25 (14) Nodal metastasis 222 (48) 86 (49) Poor differentiation 6 (1) 8 (5) Dirty necrosis (c) 431 (93) 155 (89) Crohn-like lymphoid 238 (51) 81 (47) reaction (c) Luminal serration (c) 10 (2) 12 (7) Mucin production (c) 85 (18) 53 (31) Medullary appearance (c) 0 0 BRAF mutation (n = 730) 19 (4) 13 (8) KRAS mutation (n = 696) 107 (24) 53 (32) TP53 loss or 370(82) 138 (81) overexpression (d) (n = 719) KRT20 loss (e) (n = 727) 17 (4) 7 (4) CDX2 loss (e) (n = 727) 7 (2) 11 (6) CIMP-L,0/ CIMP-H/ MSI-H, Non-MSI-H, No. (%) No. (%) (n = 46, 6%) (n = 31,4%) Age, average, y 52.5 61.2 Female 20 (44) 16 (52) Right-sided colon location 24 (52) 19 (61) Stage III or IV 16 (35) 25 (81) Distant metastasis 3 (7) 11 (36) Nodal metastasis 14 (30) 25 (81) Poor differentiation 3 (7) 8 (26) Dirty necrosis (c) 34 (74) 28 (90) Crohn-like lymphoid 36 (78) 14 (45) reaction (c) Luminal serration (c) 7 (15) 6 (19) Mucin production (c) 29 (63) 12 (39) Medullary appearance (c) 1 (2) 1 (3) BRAF mutation (n = 730) 1 (2) 5 (17) KRAS mutation (n = 696) 10 (22) 8 (30) TP53 loss or 23 (51) 26 (84) overexpression (d) (n = 719) KRT20 loss (e) (n = 727) 3 (7) 1 (3) CDX2 loss (e) (n = 727) 2 (5) 8 (28) CIMP-H/ MSI-H, No. (%) (n = 19, 3%) P Value (b) Age, average, y 68.8 <.001 Female 8 (42) .63 Right-sided colon location 14 (74) <.001 Stage III or IV 12 (63) .002 Distant metastasis 2 (11) .01 Nodal metastasis 12 (63) <.001 Poor differentiation 4 (21) <.001 Dirty necrosis (c) 11 (58) <.001 Crohn-like lymphoid 15 (79) <.001 reaction (c) Luminal serration (c) 7 (37) <.001 Mucin production (c) 15 (79) <.001 Medullary appearance (c) 3 (16) <.001 BRAF mutation (n = 730) 3 (16) .005 KRAS mutation (n = 696) 4 (22) .37 TP53 loss or 6 (32) <.001 overexpression (d) (n = 719) KRT20 loss (e) (n = 727) 7 (37) <.001 CDX2 loss (e) (n = 727) 11 (58) <.001 Abbreviations: ANOVA, analysis of variance; CIMP, CpG island methylator phenotype. (a) A total of 734 cases of colorectal cancers were analyzed. (b) An ANOVA test was conducted to compare the mean value among groups and a [chi square] test was performed to compare the other parameters. (c) If the analyzed feature was present in more than 5% of the entire tumor area, the feature was considered to be present. (d) By immunohistochemistry, loss of nuclear expression or overexpression of TP53 in all tumor cells of a tissue microarray core. (e) By immunohistochemistry, KRT20 loss and CDX2 loss were considered to be present if loss of expression was present in more than 90% of tumor cells in a tissue microarray core. Table 2. Summary of Studies Exploring the Prognostic Value of Molecular Subtypes of Colorectal Cancers (CRCs) Based on CIMP and Microsatellite Instability (MSI) Statuses in Colorectal Cancers Source, y Patients Adjuvant Ward et al, (54) 612 stage I-IV Surgery only or 2003 CRCs FU-based regimen or radiotherapy Lee et al, (55) 134 stage I-IV Surgery only or 2008 CRCs FU-based regimen Kim et al, (44) 318 stage I-IV Surgery only or 2009 CRCs FU-based regimen Ogino et al, (56) 649 stage I-IV Not informed 2009 colon cancers Sanchez et al, (68) 391 stage I-IV Not informed 2009 CRCs Dahlin et al, (69) 574 stage I-IV Surgery only or 2010 CRCs FU-based regimen or radiotherapy Han et al, (58) 322 stage II-III FOLFOX 2013 CRCs Shiovitz et al, (57) 615 stage III FU/LV or IFL 2014 colon cancers Phipps et al, (35) 2080 stage I-IV Surgery only or 2015 CRCs variable treatment Sinicrope et al, 2720 stage III FOLFOX or (59) 2015 colon cancers FOLFOX + cetuximab Source, y Molecular No. of Subtypes; Markers Subtype With the Worst Outcome Ward et al, (54) CIMP (5 markers) 4 subtypes; CIMP-H- 2003 and MSI non-MSI-H Lee et al, (55) CIMP (5 markers) 4 subtypes; CIMP-H/ 2008 and MSI non-MSI-H Kim et al, (44) CIMP (5 markers) 4 subtypes; CIMP-H/ 2009 and MSI non-MSI-H Ogino et al, (56) CIMP (8 markers) 4 subtypes; CIMP- 2009 and MSI 0,L/non-MSI-H Sanchez et al, (68) CIMP (5 markers) 4 subtypes; CIMP-H/ 2009 and MSI non-MSI-H Dahlin et al, (69) CIMP (8 markers) 6 subtypes; CIMP-H/ 2010 and MSI non-MSI-H Han et al, (58) CIMP (8 markers) CDKN2A (p16) and 2013 and MSI NEUROG1 methylation Shiovitz et al, (57) CIMP (5 markers) 4 subtypes; CIMP-H/ 2014 and MSI non-MSI-H in FU/ LV setting Phipps et al, (35) CIMP (5 markers), 5 subtypes; CIMP-H/ 2015 KRAS, BRAF, MSI non-MSI-H/BRAF mutation Sinicrope et al, KRAS, BRAF, MSI 5 subtypes; non- (59) 2015 MSI-H and mutations of either KRAS or BRAF Source, y Survival Ward et al, (54) OS and 2003 DFS Lee et al, (55) OS 2008 Kim et al, (44) OS 2009 Ogino et al, (56) CSS and 2009 OS Sanchez et al, (68) OS 2009 Dahlin et al, (69) CSS 2010 Han et al, (58) DFS 2013 Shiovitz et al, (57) OS and 2014 DFS Phipps et al, (35) CSS and 2015 OS Sinicrope et al, DFS (59) 2015 Abbreviations: CIMP, CpG island methylator phenotype; CIMP-H, CIMP-high; CIMP-0,L, CIMP-negative or-low; CSS, cancer-specific survival; DFS, disease-free survival; FOLFOX, FU plus LV plus oxaliplatin; FU, fluorouracil; IFL, FU plus LV plus irinotecan; LV, leucovorin; MSI-H, MSI-high; OS, overall survival.
|Printer friendly Cite/link Email Feedback|
|Author:||Bae, Jeong Mo; Kim, Jung Ho; Kang, Gyeong Hoon|
|Publication:||Archives of Pathology & Laboratory Medicine|
|Date:||May 1, 2016|
|Previous Article:||Clinical Aspects of Idiopathic Inflammatory Bowel Disease: A Review for Pathologists.|
|Next Article:||Recent Updates on Neuroendocrine Tumors From the Gastrointestinal and Pancreatobiliary Tracts.|