Polymorphisms in nucleotide excision repair genes, arsenic exposure, and non-melanoma skin cancer in New Hampshire.Arsenic, classified as a human carcinogen carcinogen: see cancer. carcinogen Agent that can cause cancer. Exposure to one or more carcinogens, including certain chemicals, radiation, and certain viruses, can initiate cancer under conditions not completely understood. , is a pervasive, naturally occurring mineral [International Agency for Research on Cancer The International Agency for Research on Cancer (IARC, or CIRC in its French acronym) is an intergovernmental agency forming part of the World Health Organisation of the United Nations. Its main offices are in Lyon, France. 2004; U.S. Environmental Protection Agency Environmental Protection Agency (EPA), independent agency of the U.S. government, with headquarters in Washington, D.C. It was established in 1970 to reduce and control air and water pollution, noise pollution, and radiation and to ensure the safe handling and (EPA EPA eicosapentaenoic acid. EPA abbr. eicosapentaenoic acid EPA, n.pr See acid, eicosapentaenoic. EPA, n. ) 2001]. A common route of exposure is through groundwater, where arsenic leaches in from surrounding rock. Countries with high endemic arsenic in groundwater have provided evidence of an association between arsenic and nonmelanoma skin cancer nonmelanoma skin cancer 1 Basal cell carcinoma, see there 2 Squamous cell cancer, see there 3. Skin adnexal carcinoma 4. Cutaneous lymphoma (NMSC NMSC National Merit Scholarship Corporation NMSC Non-Melanoma Skin Cancer NMSC National Marine Safety Committee (Australia) NMSC National Main Street Center NMSC Non-Metallic Sheathed Cable ) as well as precursor skin lesions Skin Lesions Definition A skin lesion is a superficial growth or patch of the skin that does not resemble the area surrounding it. Description Skin lesions can be grouped into two categories: primary and secondary. such as hyperkeratosis hyperkeratosis /hy·per·ker·a·to·sis/ (-ker?ah-to´sis) 1. hypertrophy of the stratum corneum of the skin, or any disease so characterized. 2. hypertrophy of the cornea. . For example, ecologic studies in Taiwan reported a dose-response relationship between arsenic in groundwater and prevalence of skin conditions, including NMSC (Chen et al. 1985; Hsueh et al. 1995; Tseng et al. 1968). A cohort study in this same area also observed a dose-response relationship with incidence of NMSC (Hsueh et al. 1997). Moreover, an association between NMSC and arsenic in drinking water drinking water supply of water available to animals for drinking supplied via nipples, in troughs, dams, ponds and larger natural water sources; an insufficient supply leads to dehydration; it can be the source of infection, e.g. leptospirosis, salmonellosis, or of poisoning, e.g. was reported for studies in Silesia Silesia (sĭlē`zhə, –shə, sī–), Czech Slezsko, Ger. Schlesien, Pol. Śląsk, region of E central Europe, extending along both banks of the Oder River and bounded in the south by the , Argentina, Mexico, and Chile (Bergoglio 1964; Cebrian et al. 1983; Guo et al. 1997; Jackson and Grainge 1975; Zaldivar 1974). However, in the United States, arsenic concentrations in drinking water are much lower. Municipal water is regulated by the U.S. EPA, with the standard presently set at 10 [micro]g/L (U.S. EPA 2001); however, private sources of water (defined as serving fewer than 15 households or 25 individuals) are not required to meet this standard. In New Hampshire New Hampshire, one of the New England states of the NE United States. It is bordered by Massachusetts (S), Vermont, with the Connecticut R. forming the boundary (W), the Canadian province of Quebec (NW), and Maine and a short strip of the Atlantic Ocean (E). , approximately 40% of residents have a private source of drinking water (Karagas et al. 2002). A previous analysis of NMSC and arsenic exposure in New Hampshire found an elevated risk associated with the highest concentrations of exposure (Karagas et al. 2001). It has been hypothesized that arsenic acts as a skin carcinogen by enhancing the effects of ultraviolet (UV) radiation (Hartwig 1998; Rossman 2003). In vitro in vitro /in vi·tro/ (in ve´tro) [L.] within a glass; observable in a test tube; in an artificial environment. in vi·tro adj. In an artificial environment outside a living organism. studies have demonstrated that arsenic inhibits the ligation ligation /li·ga·tion/ (li-ga´shun) the application of a ligature. tubal ligation sterilization of the female by constricting, severing, or crushing the uterine tubes. (Hartwig 1998; Hartwig et al. 1997; Lee-Chen et al. 1992) and incision steps of nucleotide excision repair Nucleotide excision repair is a DNA repair mechanism. DNA constantly requires repair due to damage that can occur to bases from a vast variety of sources including chemicals but also ultraviolet (UV) light from the sun. (NER), even at low concentrations (Hartwig 1998; Hartwig et al. 1997). Others have shown inorganic arsenic to be only weakly mutagenic mutagenic inducing genetic mutation. , whereas DNA DNA: see nucleic acid. DNA or deoxyribonucleic acid One of two types of nucleic acid (the other is RNA); a complex organic compound found in all living cells and many viruses. It is the chemical substance of genes. damage and mutation frequency after exposure to both arsenic and UV radiation is more than additive (Danaee et al. 2004). Although many biologic pathways may be disrupted by arsenic exposure, including interfering with the cell cycle activities of p53 or inhibiting base excision repair Base excision repair (BER) is a cellular mechanism that can repair damaged DNA during DNA replication. Repairing DNA sequence errors is necessary so that mutations are not induced during replication. through reduced DNA ligase DNA ligase /DNA li·gase/ (li´gas) a ligase that catalyzes the linkage between two free ends of double-stranded DNA chains by forming a phosphodiester bond between them, as in the repair of damaged DNA. III or poly-(ADP-ribose)polymerase activity (Li and Rossman 1989a, 1989b, 1991; Vogt and Rossman 2001; Yager and Wiencke 1997), the most compelling candidate for NMSC among Caucasians is the NER pathway, given the specificity of NER to repair damage from exposure to UV radiation. Epidemiologic studies have examined the relationship of polymorphisms in the NER genes Xeroderma pigmentosum xeroderma pig·men·to·sum n. A rare hereditary skin disorder caused by a defect in the enzymes that repair DNA damaged by ultraviolet light and resulting in hypersensitivity to the carcinogenic effect of ultraviolet light. groups A and D [XPA XPA Xeroderma Pigmentosum, Complementation Group A (protien) XPA X Public Access XPA Extra Points Attempted (football) and XPD XPD Palladium Ounces XPD X-Ray Photoelectron Diffraction XPD Expedite XPD Cross Polarization Discrimination XPD ATC Transponder XPD Palladium Exchange Rate (ounces) ; Unigene accession numbers P23025, S10888, respectively (Unigene 2007)] and cancer risk. The A23G polymorphism in XPA (rs1800975), located four nucleotides upstream of the start codon, has been reported to influence the risk of lung cancer lung cancer, cancer that originates in the tissues of the lungs. Lung cancer is the leading cause of cancer death in the United States in both men and women. Like other cancers, lung cancer occurs after repeated insults to the genetic material of the cell. and NMSC (Butkiewicz et al. 2004; Miller et al. 2006; Park et al. 2002; Popanda et al. 2004; Wu et al. 2003). This polymorphism is located in the Kozak sequence, and coding changes in this region are thought to influence protein levels (Kozak 1987, 1996). In fact, having one or more copies of the wild-type G allele allele (əlēl`): see genetics. allele Any one of two or more alternative forms of a gene that may occur alternatively at a given site on a chromosome. for this polymorphism has been reported to lead to significantly higher DNA repair capacity (DRC DRC Democratic Republic of Congo DRC Down (Stage) Right Center DRC Director(ate) of Reserve Components DRC Disability Rights Commission (United Kingdom) ), as determined by the host-cell reactivation reactivation to become active after a period of quiescence or, as in bacterial and viral infections, latency. cross reactivation assay (Wu et al. 2003). The reduced repair phenotype has been associated with risk of NMSC and other cancers (Berwick and Vineis 2000; Wei et al. 1994). We have previously demonstrated that this single polymorphism captures risk information for the XPA haplotype haplotype /hap·lo·type/ (-tip) the group of alleles of linked genes, e.g., the HLA complex, contributed by either parent; the haploid genetic constitution contributed by either parent. hap·lo·type n. in NMSC, and that the A allele is associated with reduced risk of both basal and squamous cell carcinomas (BCC (Blind Carbon Copy) The field in an e-mail header that names additional recipients for the message. It is similar to carbon copy (cc), but the names do not appear in the recipient's message. Not all e-mail systems support the bcc feature. See fcc. and SCC SCC - strongly connected component , respectively) (Miller et al. 2006). Polymorphisms in XPD have also been associated with DRC and NMSC susceptibility, with particular emphasis on two nonsynonymous polymorphisms: Asp312Asn (G[right arrow]A; rs1799793) polymorphism in exon Exon In split genes, a portion that is included in the ribonucleic acid (RNA) transcript of a gene and survives processing of the RNA in the cell nucleus to become part of a spliced messenger RNA (mRNA) or structural RNA in the cell cytoplasm. 10 and Lys751Gln (A[right arrow]C; rs13181) in exon 23. The wild-type alleles for these polymorphisms were found to have better DRC than the variants as determined by the host-cell reactivation assay (Spitz spitz Any of several northern dogs, including the chow chow, Pomeranian, and Samoyed, characterized by a dense, long coat, erect pointed ears, and a tail that curves over the back. In the U.S. et al. 2001), although other studies containing fewer subjects did not observe the same relationship between these polymorphisms and DNA repair (Duell et al. 2000; Lunn et al. 2000; Moller et al. 1998). However, when these polymorphisms were examined jointly (i.e., haplotypes), alleles with multiple variants were consistently observed at greater frequency among controls than BCC or SCC cases (Han et al. 2005; Lovatt et al. 2005). However, the evidence was less strong when these polymorphisms were investigated singly (Dybdahl et al. 1999; Festa et al. 2005; Vogel et al. 2001). Results from Denmark have consistently found a nonsynonymous polymorphism at codon codon: see nucleic acid. 156 to be associated with NMSC (Dybdahl 1999; Lovatt et al. 2005; Vogel et al. 2001, 2005). The hypothesis that XPD polymorphisms interact with arsenic in skin lesions has been tested in Bangladesh, where substantially elevated groundwater levels of arsenic occur. In this previous study (Ahsan et al. 2003), the increased risk of hyperkeratosis associated with arsenic exposure was stronger among those with the Lys/Lys genotype. In the current study we have extended these observations to test whether two polymorphisms in XPD, and variation in XPA, modify the skin cancer risk associated with arsenic in a U.S. Caucasian population. Materials and Methods Study population. Cases of primary invasive SCC and BCC were identified through a collaboration with dermatologists and pathologists serving the population of New Hampshire (Karagas et al. 1999). We selected New Hampshire residents between 25 and 74 years of age who were diagnosed with SCC or BCC between 1 July 1993 and 30 June 1995 (series 1) and between 1 July 1997 and 30 March 2000 (series 2). Participants were required to have an identifiable telephone number and speak English to be eligible. We identified all potentially eligible cases of SCC and, for efficiency, randomly selected a sample of BCC cases (stratified stratified /strat·i·fied/ (strat´i-fid) formed or arranged in layers. strat·i·fied adj. Arranged in the form of layers or strata. on age, sex, and anatomic site to ensure representativeness of the entire BCC group) in ratios of approximately 2:1 in the first series and 1:1 in the second series. Potential controls less than 65 years of age were chosen from the New Hampshire Department of Transportation driver's license files of state residents, and those 65 years and older were identified through the Center for Medicare and Medicaid Medicare and Medicaid U.S. government programs in effect since 1966. Medicare covers most people 65 or older and those with long-term disabilities. Part A, a hospital insurance plan, also pays for home health visits and hospice care. Services files of New Hampshire residents enrolled in Medicare. Controls were frequency-matched to the combined BCC and SCC case distribution on sex and age (25-35, 36-45, 46-50, 51-59, 60-64, 65-69, 70-74 years). The Committee for the Protection of Human Subjects of Dartmouth College approved the study, and participants provided written informed consent according to the approved protocol. Participants were interviewed, usually in their home, to obtain information on demographic factors (e.g., ethnicity, education), sun exposures (e.g., number of severe sunburns), and UV sensitivity (e.g., tendency to tan or burn). To minimize potential reporting biases, interviewers and participants were blinded to study hypotheses, and interviewers were blinded to case-control status of participants. More detailed information on data collected in the interview is provided elsewhere (Miller et al. 2006). Toenail toenail /toe·nail/ (to´nal) the nail on any of the digits of the foot. ingrown toenail see under nail. toe·nail n. arsenic. To obtain a biomarker of ingested arsenic, toenail clippings from study participants were obtained. Arsenic was measured using instrumental neutron activation analysis Neutron Activation Analysis (NAA) is a nuclear process used for determining certain concentrations of elements in a vast amount of materials. NAA allows discrete sampling of elements as it disregards the chemical form of a sample, and focuses solely on its nucleus. at the University of Missouri Research Reactor Center The University of Missouri Research Reactor Center (MURR) is home to a tank-type nuclear research reactor that serves the University of Missouri–Columbia's Nuclear Science and Engineering Institute (NSEI). . This method has been described in detail by Nichols et al. (1998). Briefly, samples first were washed to remove external contamination. Quality controls consisted of matrix-matched samples with known content and analytical blanks. The coefficient of variation Coefficient of Variation A measure of investment risk that defines risk as the standard deviation per unit of expected return. between assays was 8% (Karagas et al. 2001). The detection limit for arsenic was 0.001 [micro]g/g. All samples were blinded to case-control status. Genotyping. At the time of interview, blood specimens were collected for DNA extraction. In cases where it was not possible to collect a blood specimen, a buccal buc·cal adj. 1. Of, relating to, adjacent to, or in the direction of the cheek. 2. Of or relating to the mouth cavity. buccal specimen was retrieved. To extract buccal cell DNA, mouthwash mouthwash /mouth·wash/ (mouth´wosh) a solution for rinsing the mouth. mouth·wash n. A medicated liquid for cleaning the mouth and treating diseased mucous membranes. rinses were centrifuged at 3,200 rpm for 15 min to pellet buccal cells, followed by a wash of 15 mL TE (Tris-EDTA) buffer and spinning for 15-20 sec to resuspend Verb 1. resuspend - put back into suspension; "resuspend particles" chemical science, chemistry - the science of matter; the branch of the natural sciences dealing with the composition of substances and their properties and reactions pellet. DNA was extracted from buffy coat buf·fy coat n. The upper, lighter portion of the blood clot occurring when coagulation is delayed or when blood has been centrifuged. Buffy coat and buccal cell pellets with QIAamp DNA extraction kits (Qiagen, Valencia, CA). ABI Abi (ā`bī) [short for Abijah], in the Bible, King Hezekiah's mother. (Application Binary Interface) A specification for a specific hardware platform combined with the operating system. Taqman chemistry was used to genotype the three NER polymorphisms on an ABI7000 (XPA: G?A (-4) (rs1800975); XPD: Asp312Asn (rs1799793) and Lys751Gln (rs13181)). Taqman primers, probes, and conditions are available upon request. For quality assurance, positive and negative controls were used in each genotyping run, and 20% of samples were imbedded duplicates. Laboratory personnel were blinded to case-control status. Statistical analysis. All analyses were conducted separately for BCC and SCC cases. The genotype frequency for each polymorphism was tested for Hardy-Weinberg equilibrium. Unconditional logistic regression models generated odds ratios (ORs) and 95% confidence intervals (CIs) to examine the relationship between each NER polymorphism in the two case groups compared with controls. Multivariate models controlled for age and sex, along with number of severe sunburns, and a pigment score. The pigment score was generated as a multivariate confounder score (Cook and Goldman 1989; Miettinen 1976). A higher pigment score was consistent with lighter pigmentation pigmentation, name for the coloring matter found in certain plant and animal cells and for the color produced thereby. Pigmentation occurs in nearly all living organisms. , which leads to higher UV exposure in keratinocytes Keratinocytes Cells found in the epidermis. The keratinocytes at the outer surface of the epidermis are dead and form a tough protective layer. The cells underneath divide to replenish the supply. (target cells for NMSC). As described by Miller et al. (2006), the pigment score summarized the contribution of multiple potential risk factors, including skin reaction to first hour of intense sunshine (tan only, mild burn then tan, burn), skin reaction to repeated sun exposure (deep tan, moderately tan, mild tan and peel, freckling or no tan), hair color (dark brown/black, light brown, red, blond), eye color (brown/black, green/hazel, blue/gray), skin color (medium/dark, light), and number of moles on back (0, 1, 2-4, [greater than or equal to] 5) into a single variable. This score was included in the models of interest as quartiles, as determined by the distribution in controls. We modeled the main effects of the NER polymorphisms with genotypes dichotomized as homozygous ho·mo·zy·gous adj. Having the same alleles at one or more gene loci on homologous chromosome segments. Homozygous Identical genes controlling a specified inherited trait. wild-type compared with heterozygous het·er·o·zy·gous adj. 1. Having different alleles at one or more corresponding chromosomal loci. 2. Of or relating to a heterozygote. and homozygous variant. Based on prior work in which we observed an elevated risk at the upper end of the exposure distribution (Karagas et al. 2002), we dichotomized exposure at [less than or equal to]0.286 [micro]g/g to examine gene- environment interactions. The joint effects between the polymorphisms and arsenic were modeled, using the homozygous wild-type low arsenic (less than or equal to]0.286 [micro]g/g) as the reference category and the ORs and 95% CIs for the remaining genotype-arsenic categories were estimated. To test for statistical interaction, logistic models logistic models, n.pl statistical models that describe the relationship between a qualitative dependent variable (that is, one that can take only certain discrete values, such as the presence or absence of a disease) and an independent variable. included separate terms for arsenic and genotype and also contained their cross products. The likelihood ratio tests were conducted leaving off the cross products and comparing the -2 log likelihoods from these models. Further, it has been suggested that arsenic-induced NMSC may be more likely to develop on low-UV exposure regions of the skin (Castren et al. 1998; Tapio and Grosche 2006). To examine this in our data, tumors were determined to occur on a high UV-exposure site (e.g., head or neck) or a sun-protected site. However, our results did not differ by tumor location (data not shown). Statistics were generated using SAS (1) (SAS Institute Inc., Cary, NC, www.sas.com) A software company that specializes in data warehousing and decision support software based on the SAS System. Founded in 1976, SAS is one of the world's largest privately held software companies. See SAS System. (version 9.1; SAS Institute Inc., Cary, NC). All tests were twosided, and a p-value of 0.05 was considered statistically significant. A total of 1,181 BCC, 833 SCC, and 1,066 controls participated in the study (participation in series 1: 82% of cases and 69% of controls; participation in series 2: 81% of cases and 76% of controls). Subjects provided DNA samples from blood and/or buccal specimens (86% of series 1 and 85% of series 2 subjects). Ninety-eight percent of subjects provided toenail samples. Because the etiology for NMSC may vary by race and because of the low numbers of non-Caucasians identified, we restricted this analysis to Caucasians. Only Caucasians with both genotyping and toenail arsenic data available were included in this analysis (780 controls, 880 BCC, and 666 SCC). Results The majority of BCC and SCC cases were male and overall were approximately 60 years of age. After adjusting for age and sex, the number of severe sunburns was significantly higher among both BCC (p < 0.01) and SCC (p < 0.01) cases than controls, and pigment score also was higher among NMSC case groups than controls (BCC, p < 0.01; SCC, p < 0.01) (Table 1). There were no meaningful differences in the distribution of these characteristics for subjects who provided DNA and toenail specimens compared with those who did not (data not shown). For all three polymorphisms, the distribution of the genotypes in controls was in HardyWeinberg equilibrium. The main effect models for NER genotypes are presented in Table 2. In the XPA A23G polymorphism model, BCC and SCC cases were less likely than controls to carry one or two copies of the variant A allele (BCC: OR = 0.8, 95% CI, 0.7-1.0; SCC: OR = 0.8, 95% CI, 0.7-1.0), and these differences were of borderline significance, as described previously (Miller et al. 2006). Similarly, for the Asp312Asn polymorphism in XPD, genotypes containing the variant allele were less frequent in both case groups, and this was of borderline significance (BCC: OR = 0.8, 95% CI, 0.7-1.0; SCC: OR = 0.8, 95% CI, 0.6-1.0). However, the Lys751Gln in this same gene suggested no association with either BCC or SCC (BCC: OR = 0.9, 95% CI, 0.7-1.1; SCC: OR = 0.9, 95% CI, 0.7-1.1). Estimates of the joint effects of genotypes and arsenic are provided in Table 3. For XPA, subjects with homozygous wild-type genotypes and high arsenic (> 0.286 [micro]g/g) had an elevated risk for BCC compared with the homozygous wild-type with lower arsenic (XPA: OR = 1.8; 95% CI, 0.9-3.7), although the test for interaction was not statistically significant (p = 0.24). The test for interaction suggested that the two polymorphisms in XPD were the stronger modifiers of the association between arsenic and NMSC; the Asp312Asn polymorphism-arsenic interaction was of borderline significance for SCC (p = 0.08), and the Lys751Gln polymorphism-arsenic interaction was statistically significant for SCC (p = 0.03). For these two polymorphisms, the risk of SCC was stronger among carriers of the variant with high arsenic compared with the homozygous wild-type with high arsenic.
Table 1. Selected characteristics of basal cell carcinoma (n = 880) and
squamous cell carcinoma (n = 666) cases and controls (n = 780) on whom
toenail arsenic and genotype data were available.
Characteristic Controls BCC SCC
[n (%)] [n (%)] [n (%)]
Sex
Male 478 (61.3) 498 (56.6) 423 (63.5)
Female 302 (38.7) 382 (43.4) 243 (36.5)
Mean age (years [+ or -] SD) 61.2 58.8 64.1
[+ or -] [+ or -] [+ or -]
10.5 11.1 8.7
Severe sunburns (a)
0-2 471 (61.3) 402 (46.2) 311 (47.4)
[greater than or equal to] 3 297 (38.7) 469 (53.8) 345 (52.6)
Pigment score (b), (c)
Quartile 1 195 (25.0) 83 (9.4) 66 (9.9)
Quartile 2 197 (25.3) 173 (19.7) 114 (17.1)
Quartile 3 198 (25.4) 244 (27.7) 179 (26.9)
Quartile 4 190 (24.4) 380 (43.2) 307 (46.1)
(a) Missing sunburn information: 12 controls, 9 BCC, 10 SCC.
(b) Pigment score was generated using a multivariate confounder score
and combined data on the following pigment factors: skin reaction to
first hour of intense sunshine; skin reaction to repeated sun exposure,
hair color, eye color, skin color, and number of moles on back; higher
pigment score represented lower pigmentation and melanin production.
(c) The distribution of pigment score in controls represents the
average for the pigment score in controls as generated separately for
BCC and SCC.
Table 2. Association between nucleotide excision repair polymorphisms
and NMSC.
Gene, polymorphism Controls BCC [n OR (95% SCC [n OR (95%
[n (%)] (%)] CI)a (%)] CI)a
XPA, A23G n = 773 n = n =
868 662
GG 347 428 Referent 322 Referent
(44.9) (49.3) (48.6)
AG, AA 426 440 0.8 340 0.8
(55.1) (50.7) (0.7-1.0) (51.4) (0.7-1.0)
A allele frequency 34.1 30.8 31.1
(%)
XPD, Asp312Asn n = 728 n = n =
782 631
Asp/Asp 301 347 Referent 286 Referent
(41.4) (44.4) (45.3)
Asp/Asn, Asn/Asn 427 435 0.8 345 0.8
(58.7) (55.6) (0.7-1.0) (54.7) (0.6-1.0)
Asn frequency (%) 35.1 33.8 32.9
XPD, Lys751Gln n = 753 n = n =
854 644
Lys/Lys 322 395 Referent 289 Referent
(42.8) (46.3) (44.9)
Lys/Gln, Gln/Gln 431 459 0.9 355 0.9
(57.2) (53.8) (0.7-1.1) (55.1) (0.7-1.1)
Gln frequency (%) 34.8 33.3 33.4
(a) Odds ratios controlled for age, sex, severe sunburns, and
pigmentation.
Table 3. Joint effects of toenail arsenic measurements and nucleotide
excision repair polymorphisms on risk of NMSC.
Toenail Controls BCC SCC
arsenic
Gene, ([mu]g/g) [n (%)] [n OR (95% [n OR (95%
polymorphism (%)] CI) (a) (%)] CI) (a)
XPA, A23G n = 773 n = n =
868 662
GG [less than 334 399 Referent 309 Referent
or equal (43.2) (46.0) (46.7)
to] 0.286
> 0.286 13 (1.7) 29 1.8 13 1.1
(3.3) (0.9-3.7) (2.0) (0.5-2.6)
AG, AA [less than 401 413 0.8 323 0.8
or equal (51.9) (47.6) (0.7-1.0) (48.8) (0.7-1.1)
to] 0.286
> 0.286 25 (3.2) 27 0.9 17 0.8
(3.1) (0.5-1.6) (2.6) (0.4-1.6)
p-Value for 0.24 0.79
interaction
(b)
XPD, n = 728 n = n =
Asp312Asn 782 631
Asp/Asp [less than 282 320 Referent 276 Referent
or equal (38.7) (40.9) (43.7)
to] 0.286
> 0.286 19 (2.6) 27 1.3 10 0.6
(3.4) (0.7-2.4) (1.6) (0.3-1.3)
Asp/Asn, [less than 409 411 0.8 326 0.8
Asn/Asn or equal (56.2) (52.6) (0.7-1.0) (51.7) (0.6-1.0)
to] 0.286
> 0.286 18 (2.5) 24 1.2 19 1.2
(3.1) (0.6-2.2) (3.0) (0.6-2.4)
p-Value for 0.82 0.08
interaction
(b)
XPD, n = 753 n = n =
Lys751Gln 854 644
Lys/Lys [less than 303 368 Referent 280 Referent
or equal (40.2) (43.1) (43.5)
to] 0.286
> 0.286 19 (2.5) 27 1.2 9 0.6
(3.2) (0.6-2.2) (1.4) (0.2-1.3)
Lys/Gln, [less than 416 431 0.8 336 0.8
Gln/Gln or equal (55.3) (50.5) (0.7-1.0) (52.2) (0.6-1.0)
to] 0.286
> 0.286 15 (2.0) 28 1.6 19 1.6
(3.3) (0.8-3.2) (2.9) (0.8-3.4)
p-Value for 0.31 0.03
interaction
(b)
(a) Odds ratios controlled for age, sex, severe sunburns, and
pigmentation. (b) From test of interaction with 1 df.
Table 4. Combination of XPD polymorphisms Asp312Asn and Lys751Gln and
risk of NMSC in BCC (n = 771), and SCC (n = 617), and controls
(n = 710).
Controls BCC
XPD 312 XPD 751 [n (%)] [n (%)]
Asp/Asp Lys/Lys 236 (33.2) 271 (35.2)
Lys/Gln, Gln/Gln 60 (8.5) 72 (9.3)
Asp/Asn, Asn/Asn Lys/Lys 55 (7.8) 79 (10.3)
Lys/Gln, Gln/Gln 359 (50.6) 349 (45.3)
SCC
XPD 312 OR (95% CI)a [n (%)] OR (95% CI) (a)
Asp/Asp Referent 221 (35.8) Referent
1.0 (0.7-1.6) 60 (9.7) 1.1 (0.7-1.6)
Asp/Asn, Asn/Asn 1.1 (0.7-1.7) 53 (8.6) 1.0 (0.6-1.6)
0.8 (0.6-1.0) 283 (45.9) 0.8 (0.6-1.0)
(2) Odds ratios controlled for age, sex, severe sunburns, and
pigmentation.
Table 5. XPD polymorphisms Asp312Asn and Lys751Gln, toenail arsenic,
and risk of NMSC in BCC (n = 771), SCC (n = 617), and controls
(n = 710).
Toenail arsenic ([micro]g/g) XPD 312 XPD 751
[lesser than or equal to]?0.286 Asp/Asp Lys/Lys
Lys/Gln, Gln/Gln
Asp/Asn, Asn/Asn Lys/Lys
Lys/Gln, Gln/Gln
> 0.286 Asp/Asp Lys/Lys
Lys/Gln, Gln/Gln
Asp/Asn, Asn/Asn Lys/Lys
Lys/Gln, Gln/Gln
Toenail arsenic ([micro]g/g) Controls [n (%)] BCC [n (%)]
[lesser than or equal to]?0.286 219 (30.9) 249 (32.3)
58 (8.2) 67 (8.7)
53 (7.5) 77 (10.0)
347 (48.9) 328 (42.5)
> 0.286 17 (2.4) 22 (2.9)
2 (0.3) 5 (0.7)
2 (0.3) 2 (0.)
12 (1.7) 21 (2.7)
Toenail arsenic ([micro]g/g) OR (95% CI) (a) SCC [n (%)]
[greater than or equal to]?0.286 Referent 214 (34.7)
1.0 (0.7-1.5) 57 (9.2)
1.1 (0.7-1.7) 52 (8.4)
0.8 (0.6-1.0) 267 (43.3)
> 0.286 1.1 (0.6-2.2) 7 (1.1)
2.6 (0.5-14.7) 3 (0.5)
1.1 (0.1-7.7) 1 (0.2)
1.6 (0.7-3.4) 16 (2.6)
p-Value for interactionb 0.61
Toenail arsenic ([micro]g/g) OR (95% CI) (a)
[greater than or equal to]?0.286 Referent
1.0 (0.6-1.5)
1.0 (0.6-1.5)
0.7 (0.6-0.9)
> 0.286 0.5 (0.2-1.2)
1.4 (0.2-8.9)
0.4 (0.03-6.2)
1.7 (0.7-3.8)
p-Value for interactionb 0.07
(a) Odds ratios controlled for age, sex, severe sunburns,
and pigmentation. bFrom test for interaction (3 df) between
arsenic and the combined XPD polymorphisms at codons 312 and 751.
Discussion Previous analyses of this population have found arsenic was a potential risk factor for NMSC in the United States (Karagas et al. 2001, 2002), and the current analysis suggests that the relationship between arsenic and NMSC may be modified by NER polymorphisms. Having at least one variant at both XPD polymorphisms was observed less frequently in both BCC and SCC cases than in controls. Among these carriers of variants at multiloci, subjects with toenail arsenic > 0.286 [micro]g/g had twice the risk of SCC compared with those with lowest arsenic exposure. The results from the XPA analysis suggested that an elevated risk of BCC from exposure to high arsenic may occur in subjects homozygous wild-type for the A23G polymorphism. Previous studies have examined the XPD codon 751 polymorphism in relation to benign keratoses. In a study of residents of Bangladesh, Ahsan et al. (2003) examined the relationship between urinary arsenic, XPD Lys751Gln, and risk of hyperkeratosis, a potential precursor lesion for NMSC. The investigators found a statistically significant trend for increased arsenic-associated hyperkeratosis among those with the Lys/Lys genotype and a weaker dose response for subjects with one or two copies of the XPD codon 751 variant allele. In West Bengal India, investigators reported suboptimal Suboptimal A solution is called suboptimal if a part of the solution has been optimized without regards to the overall objective. DNA repair (as measured by frequency of chromosomal aberrations and aberrant cells) among arsenicexposed subjects with the Lys/Lys genotype compared with those with one or more variant alleles (Banerjee et al. 2007). Those with the Lys/Lys genotype also were at greater risk of hyperkeratosis. However, there are several key differences between the studies in Asia and ours from the United States. First, the minor allele frequency was higher in Bangladesh (50%) and India (40%) than in U.S. Caucasians (30%) (Ahsan et al. 2003; Banerjee et al. 2007; Shen Shen, in the Bible, place, perhaps close to Bethel, near which Samuel set up the stone Ebenezer. et al. 1998; Spitz et al. 2001). Pigmentary differences influence the amount of UV radiation exposure that reaches keratinocytes, which may alter the nature of the arsenic-gene interaction. In addition, the differences in arsenic dose may underlie the population differences in gene-environment interaction, as studies have shown that the reaction of cells to arsenic exposure differs by dose (Andrew et al. 2006; Barchowsky et al. 1999; Del Razo et al. 2001). These differences in dose are dramatic; arsenic in drinking water in Bangladesh ranges from 10 to 2,040 [micro]g/L (Tondel et al. 1999), whereas in New Hampshire the range is considerably lower (0.01-180 [micro]g/L among controls) (Karagas et al. 1998). Finally, although hyperkeratosis may be a precursor lesion for some types of keratinocyte keratinocyte /ke·rat·i·no·cyte/ (ker-at´in-o-sit) the epidermal cell that synthesizes keratin, known in its successive stages in the layers of the skin as basal cell, prickle cell, and granular cell. malignancies, in particular SCC, it is not a malignant end point. Our study included incident, histologically confirmed invasive squamous cell carcinomas. There are a number of ways that arsenic may interfere with the NER pathway and removal of DNA lesions, such as pyrimidine dimers and 6,4-photoproducts from UV radiation (Danaee et al. 2004; Hartwig 1998, 1997; Lee-Chen et al. 1992; Rossman 2003). First, NER proteins have zinc fingers, where zinc is surrounded by four cysteine cysteine (sĭs`tēn), organic compound, one of the 20 amino acids commonly found in animal proteins. Only the l-stereoisomer participates in the biosynthesis of mammalian protein. and/or histidine histidine (hĭs`tĭdēn), organic compound, one of the 22 α-amino acids commonly found in animal proteins. Only the l-stereoisomer appears in mammalian protein. residues containing sulfhydryl groups (Mackay and Crossley 1998). Arsenic has a high affinity for sulfhydryl groups, which would allow arsenic to bind to to contract; as, to bind one's self to a wife s>. See also: Bind the repair proteins. Consequently, this would inhibit the ability of NER proteins to repair DNA damage, and as a result, increase the risk of cancer. The 312 and 751 polymorphisms in XPD alter the acidity of the amino acids on the protein. If these nonsynonymous polymorphisms change protein structure, this could influence arsenic-protein binding, which may explain the mechanism of XPD polymorphism effect modification effect modification Epidemiology An interaction among multiple possible cause-and-effect relationships, where the estimate of the effect of one factor on a disease process depends on other factors in the study . Another hypothesis involves the expression of NER genes. Arsenic has been demonstrated to reduce the expression of NER genes, including the incision proteins ERCC ERCC Excision-Repair Cross-Complementing ERCC Engine(s) Running Crew Change ERCC Electric Reliability Coordinating Council ERCC Excision-Repair, Complementing Defective, in Chinese Hamster 1 and XPF XPF The ISO 4217 currency code for the CFP Franc. (Andrew et al. 2003). This reduced expression could decrease DRC, a phenotype which has been linked to cancer susceptibility, including skin cancer (Brockmoller et al. 2000; Wei et al. 1994). The polymorphisms we studied in XPA and XPD have already been linked to influencing DRC (Hemminki et al. 2001; Qiao et al. 2002a; Spitz et al. 2001; Wu et al. 2003). If arsenic influenced gene expression levels and therefore DRC, the polymorphisms may further amplify the association between arsenic and NMSC. We observed that, among those not exposed to high arsenic, subjects with genotypes containing the variant allele were at reduced risk for NMSC. This is consistent with other studies of NMSC and polymorphisms in DNA repair genes (Han et al. 2005, 2004; Marin et al. 2004; Nelson et al. 2005; Popanda et al. 2004; Sanyal et al. 2004; Shen et al. 2001). Keratinocytes are thought to have a greater apoptotic response to DNA damage than other cell types (Bowen et al. 2003). As a result, keratinocytes containing the variant allele, which may have suboptimal DNA repair compared with the wild-type (described earlier), are more likely to undergo apoptosis due to insufficient repair of DNA damage, which can reduce the risk of NMSC (Nelson et al. 2002). However, when subjects are exposed to higher concentrations of arsenic, there may be interference with cell machinery that influences DNA damage burden and the apoptotic threshold. As a result, cells with the variant allele may have more DNA damage that is not repaired and be unable to undergo apoptosis, resulting in an increased risk of NMSC. We chose to examine the relationship between arsenic, NER, and NMSC with these particular polymorphisms because previous studies found that they influenced susceptibility to various cancers. However, there are many other polymorphisms in XPA and XPD, which raises the question of whether other polymorphisms could influence these associations and should be analyzed simultaneously. For XPA, we previously conducted a haplotype analysis, accounting for coding throughout the gene (Miller et al. 2006). These results suggested that the association with NMSC susceptibility was captured by the A23G polymorphism and that haplotypes accounting for variation across XPA did not contribute more information. Therefore, we focused on the A23G polymorphism for this gene. For XPD, we chose to focus on two nonsynonous polymorphisms. We observed that the 312 and 751 polymorphisms in XPD were in linkage disequilibrium linkage disequilibrium n. The nonrandom association between two or more alleles such that certain combinations of alleles are more likely to occur together on a chromosome than other combinations of alleles. , which has been reported by other investigators (Butkiewicz et al. 2001; Caggana et al. 2001; Han et al. 2005; Hou et al. 2002; Qiao et al. 2002b; Spitz et al. 2001; Vogel et al. 2001). In addition, the combined genotype data for the two polymorphisms suggested that having coding changes at both loci together influenced risk of NMSC more than just one coding change. Therefore, our results suggest that these polymorphisms should be considered together and may identify individuals who are more susceptible to the carcinogenicity carcinogenicity /car·ci·no·ge·nic·i·ty/ (kahr?si-no-je-nis´i-te) the ability or tendency to produce cancer. carcinogenicity the ability or tendency to produce cancer. of arsenic. At this point we do not know how additional coding variation in XPD would influence this finding. By using toenail measurements of arsenic, we have a measure of arsenic intake through all routes of exposure. A limitation of this measure is that it reflects exposure at one point in time. As previously reported, this New Hampshire population was relatively stable, with over half of subjects using the same water system for at least 15 years (Karagas et al. 2001). In our study population, arsenic in toenails measured 3-5 years apart were correlated (Karagas et al. 2001), and in the Nurses' Health Study Nurses' Health Study Cardiology A large cohort study that evaluated the effect of exogenous HRT on the risk of cardiovascular disease. See Estrogen replacement therapy, Osteoporosis. measurements 6 years apart were correlated (Garland et al. 1993). In addition, because our arsenic measurements were blinded to case status, exposure misclassification would result in attenuated Attenuated Alive but weakened; an attenuated microorganism can no longer produce disease. 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XPA polymorphism associated with reduced lung cancer risk and a modulating effect on nucleotide excision repair capacity. Carcinogenesis 24:505-509. Yager JW, Wiencke JK. 1997. Inhibition of poly(ADP-ribose) polymerase by arsenite. Mutat Res 386:345-351. Zaldivar R. 1974. Arsenic contamination of drinking water and foodstuffs foodstuffs npl → comestibles mpl foodstuffs npl → denrées fpl alimentaires foodstuffs food npl → causing endemic chronic poisoning. Beitr Pathol 151:384-400. Address correspondence to M.R. Karagas, Department of Community and Family Medicine, Section of Biostatistics and Epidemiology, 1 Medical Center Dr., 7927 Rubin Building, Lebanon, NH 03756 USA. Telephone: (603) 653-9010. Fax: (603) 653-9093. E-mail: Margaret.R.Karagas@Dartmouth.edu We thank the physicians who comprise the New Hampshire Skin Cancer Study Group and the New Hampshire Society for Dermatology for their support and collaboration. This work was supported by grants R01CA082354, R01CA57494, P42 ES07373, and T32 ES07155 from the National Institutes of Health. The authors declare they have no competing financial interests. Received 22 January 2007; accepted 11 June 2007. Katie M. Applebaum, (1) (2) Margaret R. Karagas, (3) David J. Hunter, (1) (4) Paul J. Catalano, (5) (6) Steven H. Byler, (2) Steve Morris, (7) and Heather H. Nelson (2), (8) (1) Department of Epidemiology, and (2) Department of Environmental Health, Harvard School of Public Health The Harvard School of Public Health is (colloquially, HSPH) is one of the professional graduate schools of Harvard University. Located in Longwood Area of the Boston, Massachusetts neighborhood of Mission Hill, next to Harvard Medical School and Cambridge, Massachusetts, , Boston, Massachusetts, USA; (3) Section of Biostatistics and Epidemiology, Department of Community and Family Medicine, and the Norris Cotton Cancer Center NCCC is the comprehensive cancer center at Dartmouth-Hitchcock Medical Center in Lebanon, New Hampshire. It is New Hampshire's only National Cancer Institute designated comprehensive cancer center. Mark A. , Dartmouth Medical School Dartmouth Medical School is the medical school of Dartmouth College, in Hanover, New Hampshire. The school is closely affiliated with Dartmouth-Hitchcock Medical Center (DHMC) in neighboring Lebanon, New Hampshire. , Lebanon, New Hampshire
Lebanon (pronounced by natives as IPA: /ˈlεbənɨn/ or , USA; (4) Channing Laboratory, Department of Medicine, Brigham and Women's Hospital Brigham and Women's Hospital (BWH) is a hospital in the Longwood Area of the Boston, Massachusetts neighborhood of Mission Hill. With Massachusetts General Hospital, it is one of the two founding members of Partners HealthCare. and Harvard Medical School Harvard Medical School (HMS) is one of the graduate schools of Harvard University. It is a prestigious American medical school located in the Longwood Medical Area of the Mission Hill neighborhood of Boston, Massachusetts. , Boston, Massachusetts, USA; (5) Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA; (6) Department of Biostatistical Science, Dana Farber Cancer Institute, Boston, Massachusetts, USA; (7) Research Reactor Center, University of Missouri, Columbia, Missouri, USA; (8) Division of Epidemiology and Community Health, Cancer Center, University of Minnesota (body, education) University of Minnesota - The home of Gopher. http://umn.edu/. Address: Minneapolis, Minnesota, USA. , Minneapolis, Minnesota, USA |
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