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[Cancer Research 62, 4630-4636, August 15, 2002]
© 2002 American Association for Cancer Research

Epidemiology and Prevention

A Population-based Study of the Arg399Gln Polymorphism in X-Ray Repair Cross- Complementing Group 1 (XRCC1) and Risk of Pancreatic Adenocarcinoma1

Eric J. Duell2, Elizabeth A. Holly, Paige M. Bracci, John K. Wiencke and Karl T. Kelsey

Department of Cancer Cell Biology, Harvard School of Public Health, Boston, Massachusetts 02115 [E. J. D., K. T. K.], and Department of Epidemiology and Biostatistics, University of California at San Francisco, San Francisco, California 94143 [E. A. H., P. M. B., J. K. W.]


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
XRCC1 (X-ray repair cross-complementing group 1) is a base excision repair protein that plays a central role in the repair of DNA strand breaks and base damage from a variety of endogenous and exogenous oxidants including tobacco smoke. One genetic polymorphism (G->A, Arg->Gln at codon 399) occurs within a poly(ADP-ribose) polymerase binding region and within the central breast cancer susceptibility gene 1 product COOH terminus domain of XRCC1. The variant 399Gln allele of XRCC1 has been associated with elevated biomarkers of DNA damage in human cells. We conducted an analysis of the Arg399Gln polymorphism in XRCC1 using genomic DNA, and questionnaire information from 309 cases of pancreatic adenocarcinoma and 964 controls that were part of a population-based, case-control study conducted in the San Francisco Bay Area between 1994 and 2001. We genotyped individuals using a mass spectrometry-based method. Because smoking and obesity are known and suspected pancreas cancer risk factors, and have been associated with DNA damage and oxidative stress in target tissues, we estimated odds ratios (ORs), interaction contrast ratios (ICRs), and 95% confidence intervals for the combined effects of XRCC1 genotype and smoking or body mass index (in kg/m2). We also assessed potential gene-gene interactions between polymorphisms in XRCC1 and CYP1A1, GSTT1, and GSTM1. We found little or no evidence for an association between XRCC1 genotype and pancreatic cancer among Caucasians, African-Americans, or Asians. There was evidence for interaction between XRCC1 399Gln and smoking that was stronger among women than men. Relative to never active or passive smokers with the Arg/Arg genotype, the age- and race-adjusted ORs and ICRs (95% confidence limits) for heavy smoking (>=41 pack-years) were: for Gln/Gln or Arg/Gln genotypes [women OR = 7.0 (2.4, 21), ICR = 3.1 (0.03, 6.2); men OR = 2.4 (1.1, 5.0), ICR = 1.3 (-0.20, 2.8)]; and for the Arg/Arg genotype [women OR = 2.2 (0.73, 6.4); men OR = 1.5 (0.68, 3.2)]. Analyses of combined genotypes suggested an interaction between XRCC1 (Gln/Gln or Arg/Gln) and GSTT1/GSTM1-null/null among women but not among men. There was no evidence of interaction between XRCC1 genotype and body mass index. Our results suggest that the XRCC1 399Gln allele is a potentially important determinant of susceptibility to smoking-induced pancreatic cancer. Our findings, including stronger associations and interactions among women, require replication in additional study populations.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Adenocarcinoma of the exocrine pancreas is the fifth leading cause of cancer mortality among men and women in the United States (1) . The aggressive nature of most pancreas tumors combined with a lack of markers for early detection, and an unclear understanding of etiology has made this one of the deadliest of human cancers. Tobacco smoking, the only established environmental risk factor for pancreatic cancer (2) , may account for a slightly higher fraction of the disease among women (29%) than among men (26%; Ref. 3 ). Exposure to tobacco smoke has been associated with elevated oxidative stress and DNA damage endpoints in animal and human pancreata (4, 5, 6, 7, 8, 9) . Oxidative stress and lipid peroxidation also have been linked with obesity (10 , 11) , a potential risk factor for pancreatic cancer (3 , 12, 13, 14) .

DNA damage that is associated with oxidative stress is repaired by the BER3 pathway (15) . In general, BER targets endogenous oxidative DNA damage, but it also repairs strand breaks, base damage, and nonbulky adducts induced by exogenous agents such as ionizing radiation, alkylating agents, and oxidizing agents including complex carcinogens such as tobacco smoke (16) . DNA repair capacity is known to be variable in the human population, and because a part of this variation is believed to be genetic, a number of DNA repair genes have been screened recently and discovered to be polymorphic (17, 18, 19) . XRCC1 (located on 19q13.2) is a polymorphic BER gene that encodes a Mr 70,000 protein. The XRCC1 protein acts as a scaffold for interaction with other BER-associated proteins including human AP endonuclease (APE1), DNA polymerase ß, DNA ligase III, polynucleotide kinase, and PARP (20, 21, 22, 23, 24) . One polymorphism (G->A) in XRCC1 results in an arginine to glutamine change at codon 399 within a breast cancer susceptibility gene 1 product COOH terminus domain and PARP binding site (23 , 25) . The variant XRCC1 399Gln allele has been linked with DNA damage phenotypes in human tissues (26, 27, 28, 29, 30) . It also has been associated with cancer susceptibility in case-control studies of numerous cancers including head and neck, colon, stomach, lung, bladder, breast, esophagus, and skin, although results have been inconsistent with regard to at-risk alleles and definitions of exposure (31, 32, 33, 34, 35, 36, 37, 38, 39) .

We examined the role of XRCC1 as a candidate susceptibility gene for pancreatic cancer using DNA samples and exposure information collected from 309 cases of pancreatic adenocarcinoma and 964 controls from a population-based case-control study in the San Francisco Bay Area. We hypothesized that the XRCC1 399Gln allele confers an increased risk for pancreatic cancer induced by oxidative stress; namely, that having one or two copies of XRCC1 399Gln increases the effects of smoking (active smoking, duration of smoking, and smoking intensity) and obesity (elevated BMI, in kg/m2) on pancreatic cancer risk. Because age is a known risk factor for pancreatic cancer, and because we previously found significantly elevated endogenous DNA adducts among older nondiseased individuals (65 years or older) with variant XRCC1 codon 399 genotypes (Gln/Gln or Arg/Gln; Ref. 27 ), we tested the data for interactions between age and XRCC1 genotype in relation to the risk of pancreatic cancer. Finally, because alleles in XRCC1 may act synergistically with alleles in carcinogen metabolism genes to additionally increase cancer risk (40) , we examined genotype-genotype interactions between XRCC1 and the carcinogen metabolism genes GSTT1, GSTM1, and CYP1A1.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Study Population.
Patients with primary adenocarcinoma of the exocrine pancreas who were diagnosed between 1994 and 2001 were identified by the Northern California Cancer Center (Union City, CA) using rapid case ascertainment in the six San Francisco Bay Area counties of Alameda, Contra Costa, Marin, San Francisco, San Mateo, and Santa Clara. Eligible participants resided in one of the six counties at the time of diagnosis, were 21 to 85 years of age, and were alive and able to communicate in English. All of the case diagnoses were subsequently confirmed using Surveillance, Epidemiology, and End Results program abstracts. Additional out-of-area cases who met all of the study criteria other than their place of residence at the time of diagnosis were obtained through clinical files at University of California San Francisco Medical Center and were included in the full case-control study to improve sample size. The majority of these cases were from other counties in northern California. As none of the out-of-area participants was asked to provide a blood sample, these could not be included in the present analyses. Control participants were identified using RDD and the HCFA lists for those who were 65 years and older, and were frequency matched to cases by sex and age within 5-year categories. Out-of-area controls, also identified by RDD, were frequency matched to out-of-area cases by telephone area code and prefix of residence, and by sex and age. Detailed in-person interviews were conducted in the homes of the participants or at a location of their choice for Bay Area participants and by telephone interview for out-of-area participants. No proxy interviews were conducted. The University of California San Francisco institutional review board approved all of the study procedures, and written informed consent was obtained from each study participant before interview and before collection of blood for genetic analyses.

A total of 530 eligible pancreatic cancer patients were interviewed for our larger case-control study. Sixty-five percent (n = 466) of the San Francisco Bay Area pancreatic cancer cases and 80% (n = 64) of those from outside the six-county area who were eligible completed their interviews. The analyses for this study are based on 309 patients who gave blood as part of the laboratory portion of the study and whose specimens were available for genotyping. Blood was not obtained from the out-of-area cases and from the remainder of the case participants for the following reasons: patient was too ill, patient had died, patient or physician refused, or the blood draw was unsuccessful or insufficient. Among cases, there were no statistical differences (all of the Ps were >0.05) between those who provided blood and those who did not provide blood by variables for age, sex, race, education, smoking status (never, former, current), or pack-years of smoking.

A total of 1701 eligible control participants were interviewed. Of these, 59% were obtained by RDD in the six-county San Francisco Bay Area, 4% by out-of-area RDD, and 37% from HCFA lists. Sixty percent of eligible San Francisco Bay Area RDD control subjects, 69% of eligible out-of-area RDD control subjects, and 53% of eligible HCFA control participants completed interviews. Analyses presented here are based on 964 control participants who gave blood as part of the laboratory portion of the study and whose specimens were available for genotyping. Blood was not obtained from out-of-area controls and from the remainder of the control participants for the following reasons: participant refused, participant had moved since the interview, participant was ill, the blood draw was unsuccessful or insufficient, or the participant had died. Among controls, there were no statistical differences between those who provided blood and those who did not provide blood by age, education, and pack-years of smoking (all of the Ps were > 0.05). Overall, case or control status was not related to providing blood (P = 0.6). Among controls, there were statistically significant differences between those who provided blood and those who did not by race (P = 0.002, a higher proportion of Caucasian participants provided blood), sex (P = 0.002, a higher proportion of men provided blood), and smoking status (P < 0.001, a smaller proportion of never-smokers provided blood).

Exposure Information.
Exposure history was obtained at interview by self-report using structured questionnaires. No proxy interviews were conducted. The interview for all of the subjects included questions about tobacco use, alcohol consumption, diet, occupational exposures, family history, medical history, and demographic information. Race was based on self-report and was broadly defined as Caucasian, African-American, or Asian.

Participants were defined as never-smokers if they never had smoked >100 cigarettes in their lifetime and had not smoked cigars or pipes at least once per month for 6 months or more. Because there was a substantial number of participants who had never smoked and who reported a history of passive smoke exposure at home as an adult (women: 32 cases, 95 controls; men: 5 cases, 21 controls), these individuals were removed from the referent group of never-smokers. Smoking duration was defined as the total number of years of cigarette smoking. Smoking intensity (pack-years) was defined as the number of packs of cigarettes smoked per day multiplied by the number of years smoked. Cut-points for pack-years or duration of smoking were based on quartiles of the distribution among all of the control participants who smoked. Recent smoking was assessed using pack-years or duration restricted to within 15 calendar years of the date of diagnosis among cases or interview among controls.

BMI (weight in kilograms divided by height in meters squared) was based on self-reported usual adult height and weight. Cut-points for elevated BMI were based on the upper tertile (25.75 kg/m2 or more) or upper quartile (26.60 kg/m2 or more) of the distribution among the 964 controls who participated in the laboratory portion of the main study.

Laboratory Methods.
Genomic DNA was extracted from peripheral blood lymphocytes using the QIAmp DNA Blood Mini kit (Qiagen, Inc., Valencia, CA) and according to the manufacturer’s instructions. Genotyping for XRCC1 (G->A at nucleotide 28152 in exon 10, Arg->Gln at codon 399) was performed using the Masscode assay (Qiagen Genomics, Inc., Bothell, WA; Ref. 41 ). This mass spectrometry-based method uses standard PCR amplification of the region containing the polymorphism followed by hybridization with oligonucleotide primers that have been modified with photocleavable linkers attached to tags of variable composition (cleavable mass spectrometry tags) such that each allele-specific oligonucleotide primer is of different mass. For homozygotes, the mass spectrometer detects a single allele-specific tag, and for heterozygotes it detects two tags. In unpublished pilot data, we compared this mass spectrometry method with a standard PCR-RFLP method (27) using 100 samples of genomic DNA from Caucasians in the Boston area. In this comparison of two different methods for assaying the same XRCC1 Arg399Gln polymorphism, we observed no discordant pairs. For the full genotyping sample, we included a blinded 10% random sample of repeats (n = 128 pairs). Pairs discordant on genotype (n = 4; 3%) were dropped from subsequent analyses.

PCR-RFLP analysis was used to genotype CYP1A1 m1 (T->C, nucleotide 6235 in 3' flanking region), GSTM1-null (homozygous gene deletion), and GSTT1-null. Detailed methods and results of analyses of polymorphisms in CYP1A1, GSTM1, and GSTT1 in this subset of the San Francisco Bay Area pancreatic cancer study have been described previously (40) .

Statistical Methods.
Tests for Hardy-Weinberg equilibrium among controls were conducted using observed genotype frequencies and a {chi}2 test with one degree of freedom. ORs and 95% CIs were estimated using unconditional logistic regression in SAS (v. 8; SAS Institute, Cary, NC). Risk factors for pancreatic cancer and potential confounders were kept in multivariable models if their removal caused ß parameter estimates to change by >10%. Final multivariable models are presented stratified by sex and include terms for age (continuous) and race (Caucasian, African American, and Asian) unless otherwise noted. In general, ORs did not differ substantially by race, so results for combined effects of XRCC1 genotype and exposure are presented among all of the racial groups combined. Other potential confounders that were evaluated but not included in multivariable models were: alcohol consumption, coffee consumption, education (high school or less, college, graduate work), annual household income, first-degree family history of pancreatic cancer, and medical conditions (history of pancreatitis, diabetes, ulcer, gallbladder disease, allergy, and vitamin B12 deficiency). Hormonal factors and reproductive history (age at menarche, age at menopause, parity, age at first full-term birth, oral contraceptive use, and hormone replacement therapy use) were also evaluated in separate multivariable models among women. Women who reported cessation of menstrual periods at the time of interview were defined as menopausal, and women who reported their menses had begun to cease (3 cases, 12 controls) or had not ceased (8 cases, 47 controls) were categorized as premenopausal women. With the exception of age at menopause, none of these factors were identified as confounders or risk factors for pancreatic cancer among women in this subset of our San Francisco Bay Area population.

Gene-environment and gene-gene interactions were estimated by evaluating departures from additivity. Departures from additivity were evaluated by estimating multivariable ORs for the combined effect of XRCC1 codon 399 genotype and exposure (heavy smoking, elevated BMI, or older age) or genotypes for polymorphic carcinogen-metabolizing genes (CYP1A1, GSTM1, GSTT1). Variables for combined effects were coded using a common referent group (e.g., XRCC1 codon 399 Arg/Arg and never-smoker). The magnitude of an interaction effect was determined by estimating age- and race-adjusted ICRs with 95% CLs using PROC LOGISTIC in SAS (42) . We calculated the ICR using the following formula:

, where RR11 is the RR for exposure with a variant XRCC1 genotype, RR10 is the RR for a variant XRCC1 genotype among the nonexposed, and RR01 is the RR for exposure with a nonvariant XRCC1 genotype. ORs were used to estimate RRs. ICRs > 0 imply greater than additive effects (interaction), whereas ICRs of zero imply additive effects (no interaction), and ICRs < 0 imply less than additive effects (negative interaction; Ref. 43 ). For the present study, we considered ICRs of magnitude 1 or higher as indicative of an interaction. CLs for ICRs that exclude the null value of zero can be considered statistically significant at {alpha} level 0.05. For estimation of ICRs, cigarette smoking and genotypes were dichotomized using the highest quartile of pack-years or duration for smoking (for example, 41 or more pack-years versus all of the others), and variant-allele containing genotypes (variant/variant + variant/wild-type versus wild-type/wild-type), as the exposed groups.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Characteristics of this subset of the San Francisco Bay Area study population have been published previously (40) . Heavy cigarette smoking (upper quartile: 41 or more pack-years) was positively associated with pancreatic cancer (age, sex- and race-adjusted OR, 2.4; 95% CI, 1.6–3.4). ORs for cigarette smoking and pancreatic cancer were similar between women and men (data not shown). However, among women, ORs for heavy cigarette smoking increased 20% when those with passive exposure at home were removed from the referent group of nonsmokers (data not shown). A similar increase was absent among men, but fewer men reported exposure to passive cigarette smoke (5 cases and 21 controls). There was a positive but weak association between BMI (kg/m2, in tertiles <23.01, 23.01–25.74, >=25.75) and pancreatic cancer among women and men (age-, sex- and race-adjusted OR, 1.2; 95% CI, 0.84–1.6 middle compared with lower tertile; OR, 1.4; 95% CI, 0.99–1.9 upper compared with lower tertile). ORs for BMI and pancreatic cancer were similar between women and men (data not shown).

Allele and genotype frequencies and ORs for XRCC1 Arg399Gln by race are presented in Table 1Citation . A {chi}2 test of observed genotype versus expected genotype frequencies for XRCC1 was suggestive of deviations from Hardy-Weinberg equilibrium among Caucasian controls (P = 0.053; Table 1Citation ). In general, there was no evidence for a main effect of the XRCC1 Arg399Gln polymorphism on pancreatic cancer. Among African-American participants, homozygous variant genotypes were combined with heterozygous genotypes to estimate ORs because of small numbers. Among all of the participants, age- and race-adjusted ORs for XRCC1 and pancreatic cancer were higher among women (OR, 1.3; 95% CI, 0.87–2.1 heterozygotes compared with wild-types; OR, 1.6; 95% CI, 0.86–2.9 homozygous variants compared with wild-types) compared with men (OR, 0.96; 95% CI, 0.66–1.4 heterozygotes compared with wild-types; OR, 1.0; 95% CI, 0.58–1.9 homozygous variants compared with wild-types). XRCC1 genotypes were not associated with either age at diagnosis among cases or age at interview among controls of either sex or by race (data not shown).


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  		Table 1 Allele and genotype frequencies and ORs for XRCC1, stratified by race/ethnicity, San Francisco Bay Area, California 1994-2001

 
Because the results of analyses for gene effects, exposure effects, and gene-environment or gene-gene interactions did not differ substantially among the racial groups used in this study (Caucasians, African-Americans, and Asians), we have presented ORs adjusted for age and race separately for women and men, unless otherwise noted.

ORs for the combined effect of XRCC1 genotype and tobacco smoking variables are given in Table 2Citation . Among women in our study, XRCC1 genotype did not modify the effect of passive smoking exposure on pancreatic cancer. Among women who reported no active cigarette use, two controls reported pipe and/or cigar use, and the remaining women were exposed to passive smoke or were classified as "never-active or passive" smokers. Among women who reported that they were former cigarette smokers ("former-active") or current cigarette smokers ("current-active"), ORs were higher among genotypes with one or two copies of the XRCC1 399Gln allele (Arg/Gln or Gln/Gln). For the combined effect of XRCC1 genotype and number of pack-years of smoking or duration on pancreatic cancer, ORs again were higher for heavy smoking among those with one or two copies of the XRCC1 399Gln allele. Results did not substantially differ (by >10%) when pack-years or duration of smoking was restricted to within 15 calendar years of diagnosis among cases or interview among controls (data not shown).


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  		Table 2 ORs for the joint effects of tobacco smoking and XRCC1 genotype, stratified by sex, San Francisco Bay Area, California 1994–2001

 
ORs for the combined effect of XRCC1 genotype and smoking among women were stronger when age (in years) at menopause (premenopausal, <=45, 46–54, >=55) was included in multivariable models (data not in TableCitation ). The age- and race-adjusted ORs for age at menopause and pancreas cancer (relative to premenopausal women) were 1.2 (95% CI, 0.51–2.7) for ages <=45, 1.8 (95% CI, 0.82–4.1) for ages 46–54, and 2.2 (95% CI, 0.85–5.6) for ages >=55. Among women, the age-, race-, and age at menopause-adjusted OR for heavy smokers (41 or more pack-years) with the XRCC1 Gln/Gln or Arg/Gln genotype was 8.6 (95% CI, 2.9–25.8), whereas the age-, race-, and age at menopause-adjusted OR for heavy smokers with the XRCC1 Arg/Arg genotype was 2.5 (95% CI, 0.83–7.4). The age-, race-, and age at menopause-adjusted OR for light smokers (less than 41 pack-years or passive) with the XRCC1 Gln/Gln or Arg/Gln genotype was 2.2 (95% CI, 0.89–5.4), whereas the age-, race-, and age at menopause-adjusted OR for light smokers with the XRCC1 Arg/Arg genotype was 1.6 (95% CI, 0.64–3.8). The age-, race-, and age at menopause-adjusted OR for never-active/passive smokers with the XRCC1 Gln/Gln or Arg/Gln genotype was 1.4 (95% CI, 0.48–3.9).

Among men who reported no active cigarette smoking, passive smoking exposure was less common (5 cases and 21 controls) than among women. However, self-reported pipe and/or cigar use was more common among men (10 cases and 40 controls) who were never-active cigarette smokers than among women (Table 2)Citation . Among men, never-smoking and passive or cigar/pipe smoking were inversely associated with pancreatic cancer among variant 399Gln containing genotypes, possibly because of small sample size. Among men, ORs for current-active smoking and heavy smoking (>=41 pack-years or >40 years) were greater among variant genotypes (Gln/Gln or Arg/Gln) than among nonvariant genotypes. In general, combined ORs for XRCC1 genotype and smoking were stronger among women than among men (Table 2)Citation .

We estimated the magnitude of interaction effects by calculating the ICR. The age- and race-adjusted ICR and 95% CLs for smoking pack-years (>=41 versus never-active or passive smoker) and XRCC1 (Gln/Gln or Arg/Gln versus Arg/Arg) for all of the participants was 1.8 (0.47, 3.1); for women ICR = 3.1 (0.03, 6.2); for men ICR = 1.3 (-0.20, 2.8), suggesting moderate interaction effects between XRCC1 genotype and heavy smoking.

XRCC1 genotype was not associated with BMI (kg/m2, in tertiles or quartiles) among controls of either sex (Mantel-Haenszel {chi}2, all P > 0.1). We then evaluated joint ORs for BMI (tertiles or quartiles) and XRCC1 genotype, and found no evidence for association with case/control status or OR modification by sex (data not shown). Likewise, there was no evidence of elevated ORs for the combined effect of XRCC1 genotype and age (>=65 years versus <65 years) on risk of pancreatic cancer (data not shown).

ORs for the combined effect of XRCC1 and CYP1A1 m1 genotypes are presented in Table 3Citation . Among women with variant alleles for both XRCC1 and CYP1A1 m1, there was a 3-fold increased risk of pancreatic cancer compared with women with wild-type genotypes for both genes. Among men, the joint OR for CYP1A1 variant genotypes (m1/wt + m1/m1) and wild-type XRCC1 (Arg/Arg) was inversely associated with case status (Table 3)Citation . The age-, race-, and smoking-adjusted ICR and 95% CLs for XRCC1 (Gln/Gln or Arg/Gln versus Arg/Arg) and CYP1A1 (m1/m1 or m1/wt versus wt/wt) for all of the participants was 0.64 (-0.035, 1.3); for women ICR = 0.79 (-1.4, 3.0); for men ICR = 0.77 (0.045, 1.5), suggesting little or no interaction between XRCC1 and CYP1A1 genotypes.


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  		Table 3 ORs for the combined effect of XRCC1 and CYP1A1 ml genotypes, stratified by sex, San Francisco Bay Area, California 1994–2001

 
ORs for the combined effect of XRCC1 genotype and GSTM1 and/or GSTT1 homozygous gene deletion (null) genotypes are presented in Table 4Citation . There was little evidence among women or men for a combined effect of variant GSTM1 and XRCC1 genotypes. For GSTT1-null, a 2.6-fold increase in risk was observed among women (but not men) with variant XRCC1 genotypes. For the combined effect of variant XRCC1 and GSTM1-null and GSTT1-null, we observed a 3.6-fold positive association with risk of pancreatic cancer among women. The age-, race-, and smoking-adjusted ICR and 95% CLs for XRCC1 (Gln/Gln or Arg/Gln versus Arg/Arg) and GSTM1/T1 (null/null versus present/present or null/present) for all of the participants was 1.0 (-0.16, 2.2); for women ICR = 2.0 (-1.1, 5.0); for men ICR = 0.59 (-0.75, 1.9), suggesting a weak to moderate interaction between XRCC1 and GSTT1/GSTM1 genotypes.


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  		Table 4 ORs for the combined effect of XRCC1 genotype, and GSTM1 and GSTT1 deletion genotypes, stratified by sex, San Francisco Bay Area, California 19941–2001

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
We investigated the role of the XRCC1 Arg399Gln polymorphism in pancreatic adenocarcinoma in a subset of a population-based, case-control study from the San Francisco Bay Area. We found evidence for synergy between XRCC1-399Gln and cigarette smoking, in particular, current or heavy smoking (>=41 pack-years or >=40 years in duration). Because most of the heavy smokers in our study also were current smokers, it was difficult to separate the effect of high-intensity exposure from the effect of recent exposure. However, the interaction between XRCC1 and smoking was strongest when smoking was based on intensity (pack-years) suggesting dose may be as important as timing of exposure. Insofar as XRCC1 alleles are determinants of XRCC1 function and BER capacity, the observed interaction between XRCC1 codon 399 genotype and cigarette smoking suggests that XRCC1 protein and BER capacity are important in protecting pancreatic cells from the damaging effects of tobacco smoking. Furthermore, the magnitude of ORs and interaction effects consistently was stronger among women than men. Whereas the incidence of pancreas cancer is about 20–25% higher in men than in women, recent trends indicate that rates may be declining less in women than in men (44 , 45) .

There are several potential explanations for our observations including biological differences between women and men in the response to tobacco carcinogens, as well as nonbiological differences in smoking behavior and in the prevalence of unmeasured risk factors correlated with smoking (such as occupational exposures). In support of the first premise, a recent study of autoantibodies to oxidative DNA-based damage found significantly higher levels among women who smoke than among men who smoke (46) . Observational evidence suggests that estrogens may increase levels of triglycerides and total lipids in human pancreas (47 , 48) , and, thus, increase the level of reactive oxygen species and subsequent DNA damage in the pancreas. Moreover, endogenous estrogens themselves may damage DNA (49) or synergistically increase the DNA-damaging properties of tobacco smoke. Other potential biological explanations include lower DNA repair capacity in women (50) , differences in response to DNA-damaging agents between women and men (51, 52, 53) , and sex-specific expression of receptors for gastrin-releasing peptide, which has been demonstrated in pancreas cells (54) and has been hypothesized recently to play a role in observed gender differences in smoking-related lung cancer susceptibility (55) . Analogous to the lung cancer susceptibility issue, a number of previous studies of pancreatic cancer among men and women, including observations in our San Francisco Bay Area population, have reported stronger smoking-related associations among women than among men (3 , 40 , 56, 57, 58) . Because of the inherent limitations of the case-control study design, we cannot rule out the possibility that the background risk of pancreatic cancer for male never-smokers is higher than that for female never-smokers. Such a difference in background risks could contribute to the larger relative risks for smoking and pancreatic cancer among women than among men as observed in this study and in other studies (3 , 40 , 56 , 57) . However, this phenomenon is unlikely to explain all of the gender differences in relative risk for the combined effect of XRCC1 genotype and smoking, because our relative risk estimates for heavy smoking and pancreatic cancer were only 20% higher among women than among men when passive smoking was removed from the referent group of never smokers.

The mechanism by which tobacco carcinogens act in the human pancreas is currently unknown. Smoking has been associated with oxidative stress and DNA damage in animal and human pancreatic specimens (4, 5, 6, 7, 8, 9) . Thus, efficient repair of oxidative DNA damage in pancreas tissue may be important in highly exposed individuals. The Arg399Gln amino acid change occurs within the central breast cancer susceptibility gene 1 product COOH terminus domain of human XRCC1 (codons 314–402; Ref. 25 ), a protein-binding motif present in several cell cycle and repair proteins including BRCA1. This motif appears to be important in DNA damage detection, DNA end binding, multimerization, and genetic stability (59) . The Arg399Gln polymorphism also occurs within a PARP binding region (codons 301–402; Refs. 24 , 60 ). Thus, this polymorphism has the potential to influence XRCC1 function. In studies using human cells and tissues, the variant allele (399Gln) has been associated with biomarkers of DNA damage including higher glycophorin (GPA) mutant frequency (26) , elevated DNA adduct levels (26 , 27 , 30) , higher baseline sister chromatid exchange frequency (27 , 28) , and increased sensitivity to ionizing radiation as measured by prolonged mitotic delay (29) .

In analyses of genotype-genotype interaction, ORs and ICRs were strongest for combined XRCC1, GSTT1, and GSTM1 variant genotypes. Furthermore, these interactions were observed predominantly among women. The observed (age-, race-, and smoking-adjusted) interactions between XRCC1 genotype and metabolic genotypes suggest that these genes in combination may be important in determining susceptibility to pancreatic cancer irrespective of tobacco carcinogen exposure and that women could be more susceptible within a given genetic background than are men. These observations also raise the possibility that other (nontobacco) sources of carcinogens or oxidant stress play a role in pancreatic carcinogenesis. Indeed, tobacco smoking is believed to account for 26–29% of pancreatic cancer incidence (3 , 56 , 61) . However, the magnitude of such estimates of population attributable fraction may vary depending on the genetic background of the population under study, including variation in alleles of genes for carcinogen-metabolism, DNA repair, and other key biochemical pathways that may interact with constituents in tobacco smoke (40) .

We conducted tests for Hardy-Weinberg equilibrium among controls and found evidence of possible deviations for XRCC1 alleles among Caucasians. Deviations from Hardy-Weinberg equilibrium can result from systematic errors in genotyping, population stratification, or inbreeding. We cannot rule out the possibility that biased sampling may have contributed to stratification in our population sample; however, bias from stratification and inbreeding is unlikely in a dynamic and heterogeneous ("outbred") Caucasian population such as that found in the San Francisco Bay Area (62) . In unpublished pilot data, we compared the Masscode genotyping assay for XRCC1 codon 399 with a standard PCR-RFLP method (27) . In this comparison of two different genotyping methods, we observed no discordant pairs, suggesting no systematic bias for XRCC1 genotyping using the mass spectrometry-based assay. Furthermore, random error was low because the proportion of discordant pairs among all of the repeated pairs (n = 128) using this assay was 3% (n = 4). Nevertheless, because our allele and genotype frequencies for XRCC1 399Gln were lower than expected, our estimates of ORs are likely to be conservative, because the true type I error (the chance of rejecting the null hypothesis of no association when it is true) is likely lower than assumed (63) .

Potential weaknesses in our study include possible recruitment bias among pancreatic cancer cases associated with the rapidly fatal course of this disease and the potential role of chance in some gender-specific comparisons. If XRCC1 genotype is associated with lower mortality, our data are likely to underestimate the true effect of XRCC1 alleles on risk of pancreatic cancer. Whereas we cannot rule out the potential influence of systematic differences between participants and nonparticipants in the laboratory portion of the study on measures of association and interaction, these differences would also have to vary accordingly by XRCC1 genotype.

In summary, our data provide evidence for synergy between the XRCC1 399Gln allele and tobacco smoking in relation to the risk of pancreas cancer. Our finding of stronger associations and interactions among women is suggestive but requires replication in additional study populations. A number of case-control studies have evaluated the role of XRCC1 polymorphisms in human cancer including such diverse sites as head and neck, colon, stomach, esophagus, lung, bladder, breast, and skin (31, 32, 33, 34, 35, 36, 37, 38, 39) . Our results are consistent with the genotype-phenotype studies that suggest XRCC1 399Gln is the at-risk allele (26, 27, 28, 29, 30) and with some case-control studies (31, 32, 33, 34 , 39) but not with others (35, 36, 37, 38) . Inconsistencies across studies could result from variations in tissue-specific XRCC1 expression levels, exposure-specific effects of XRCC1 alleles, and competing or overlapping biochemical pathways (16 , 64) . Nevertheless, we believe that the XRCC1 codon 399 polymorphism warrants additional study in the context of cancer susceptibility, and that basic research on the function of this protein, its allelic variants, and other BER proteins should continue.


   ACKNOWLEDGMENTS
 
We thank Mei Liu and Kim Swarner for DNA sample extraction and sample management.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Supported in part by a Lustgarten Foundation for Pancreatic Cancer Research Grant and by grants CA59706, CA89726, ES00002, and ES06717 from the National Cancer Institute and National Institute of Environmental Health Sciences. Back

2 To whom requests for reprints should be addressed, at Department of Epidemiology and Social Medicine, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461. Back

3 The abbreviations used are: BER, base excision repair; BMI, body mass index; CI, confidence interval; OR, odds ratio; PARP, poly(ADP-ribose) polymerase; XRCC1, X-ray repair cross-complementing group 1; RDD, random digit dial; HCFA, Health Care Finance Administration; CL, confidence limit; ICR, interaction contrast ratio; RR, risk ratio. Back

Received 1/24/02. Accepted 6/14/02.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
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