DNA repair pathways: Genetic determinants of disparities in prostate and colon cancer.
Authors: Jennifer J. Hu
Journal: Cancer Research (2006)

SY09-02  The rapid advancement of human genome research has initiated a new era of genetic profiling for risk assessment, prevention, and treatment. As dramatic variations due to genetic background and/or environmental exposures are well established, we propose that cancer prevention may be more effective if it targets well-characterized individual risk profiles (e.g., combined genetic and environmental risk factors) with personalized strategies. Hence, well-designed population studies are needed to characterize the molecular mechanisms of gene-gene and gene-environment interactions in human cancer risk. Based on the concept that genetically susceptible (sub)populations may be more motivated for screening, early detection, and intervention, we will establish and validate gene-environment human cancer risk models and translate this information into health behavior promotion in genetically susceptible (sub)populations. African-American men have higher incident and mortality rates for prostate and colon cancers than European Americans. The mechanisms of this racial/ethnic disparity are largely unknown but probably due to interactions among genetic factors, environmental exposures, lifestyles, screening behavior, diagnosis status, and treatment. Since, in addition to germline mutations, tumor cells from the prostate and colon contain many somatic mutations, gene deletions and amplifications, chromosomal rearrangements, and changes in DNA methylation, we hypothesize that an accumulation of genetic abnormalities and a decline in DNA repair may contribute to the racial/ethnic difference in cancer risk.  Prostate cancer is the most common cancer in American men. Despite rapid advances in research, critical questions about risk and progression remain unanswered. Incidence is known to increase with age; more than 70% of all cases are diagnosed in men over 65. Race/ethnicity is also associated with differences in prostate cancer mortality rates. African Americans have a higher incidence rate, are more likely to be diagnosed at a more advanced stage, and more likely to die of it compared to whites. Still unknown is how much of this variation is due to genetic factors rather than diet, lifestyle, and environmental factors. Colon cancer is the most common gastrointestinal cancer and the second leading cause of cancer deaths in the United States. The risk of colorectal cancer generally increases with age. African Americans have a higher incidence rate, are more likely to be diagnosed at a more advanced stage, and more likely to die of it compared to whites. The major risk factors are inflammatory bowel disease, a family history of colorectal cancer or colorectal polyps, and certain hereditary syndromes.  Over the past several years, substantial evidence suggests roles for DNA-repair SNPs in identifying populations at increased risk for certain cancers. Genetic variants in the multiple pathways for repairing diverse DNA damages induced by carcinogens should be evaluated simultaneously, since they may have a joint or additive effect on cancer risk, therapy response, and recurrence. We conducted two studies to pilot test whether germline nonsynonymous coding single nucleotide polymorphisms (nsSNP) of DNA-repair genes may contribute to racial/ethnic differences in prostate or colon cancer risk and progression. We selected 20 nsSNPs in 14 DNA-repair genes of 4 repair pathways, including: (i) Base Excision Repair: ADPRT V762A, APE1 D148E, POLD1 R19H/R119H, and XRCC1 R194W/R280H/R399Q; (ii) Nucleotide Excision Repair: ERCC2 D312N/ K751Q, ERCC4 R415Q, and ERCC5 D1104H; (iii) Mismatch Repair: MLH1 I219V, MSH3 R940Q/T1036A, and MSH6 G39E; and (iv) Double-Strand Break Repair: NBS1 Q185E and XRCC3 T241M. The genomic DNA was extracted from whole blood collected in two case-control studies: a clinic-based prostate cancer study (623 cases, 646 controls) and a North Carolina population-based colon cancer study (643 cases, 1049 controls). Genotyping was performed using the MassARRAY system (SEQUENOM Inc., San Diego, CA).  The genetic risk patterns for prostate cancer differed between Caucasians and African Americans. In Caucasians, the prostate cancer risk was significantly associated with ADPRT 762 AA (OR=2.16, 95%CI=1.00–4.65), ERCC2 312 NN (OR=0.66, 95%CI=0.44–0.99), and MSH3 940 QQ (OR=3.51, 95%CI=1.27–9.74) genotypes, after adjusting for age, family history, smoking history, and benign prostatic hyperplasia. With limited sample size, we could not obtain meaningful results in African Americans using the logistic regression models. To explore potential gene-gene interactions, we used a multivariate Adaptive Regression Splines (MARS)-logit method with a hybrid data-mining approach. In Caucasians, prostate cancer risk was significantly associated with a ERCC2 312 DN/NN genotype (OR=2.19, 95%CI=1.31–3.67) and the combination of ERCC2 312 NN, XRCC3 241 TM/MM, and NBS1 185 QQ genotypes (OR=3.24, 95%CI=1.42–7.41), after adjusting for age and family history. In African Americans, prostate cancer risk was significantly associated with the combination of MSH3 940 RR and APE1 148 DD genotypes (OR=3.09, 95%CI=1.50–6.37) and the combination of MSH3 940 RR, APE1 148 DE/EE, and MSH3 1036 TA/AA genotypes (OR=2.64, 95%CI=1.13–6.18). We also evaluated whether these DNA-repair nsSNPs contribute to prostate cancer recurrence. We confirmed 3.5-year follow-up data on 446 cases. Recurrence was significantly associated with a MSH3 1036TA/AA genotype (OR=4.13, 95%CI=1.76–9.68), the combination of ERCC5 1103DD and XRCC1 280RH/HH genotypes (OR=4.57, 95%CI=1.42–14.73), or the combination of MSH3 1036TT, XRCC3 241 TM/MM and ERCC2 312 DN/NN genotypes (OR=3.22, 95%CI=1.66–6.26), after adjusting for family history, smoking history, diagnosis age, and follow-up time period.  The genetic risk patterns for colon cancer also differed between Caucasians and African Americans. In Caucasians, colon cancer risk was significantly associated with MSH3 940 QQ (OR=2.4, 95%CI=1.1–4.9), MSH3 1036 AA (OR=2.1, 95%CI=1.3–3.4), or MSH6 39 GE/EE (OR=0.6, 95%CI=0.4–0.9) genotypes, after adjusting for age, gender, folate intake, smoking history, caloric intake, and family history. In African Americans, colon cancer risk was significantly associated with an XPC 499 AV/VV (OR=1.6, 95%CI=1.0–2.5) or XPC 939 KQ/QQ (OR=0.7, 95%CI=0.5–1.0) genotype, after adjusting for age, gender, folate intake, smoking history, caloric intake, and family history. Increased consumption of well-done or charred meat was associated with increased exposure to heterocyclic aromatic amines (HAAs) or other carcinogens associated with an increased risk of colon cancer. In the same study population, African Americans consumed well-done and charred meat more often than Caucasians. These differences might explain some of the racial/ethnic differences in the genetic risk patterns (i.e., NER SNPs in African Americans vs. MMR SNPs in Caucasians), since NER pathways play critical roles in repairing DNA damages induced by HAAs.  In conclusion, gene-gene interactions of DNA-repair nsSNPs in multiple repair pathways contribute to human cancer risk, and we found racial/ethnic-specific risk patterns. However, we must note that sample size may have limited our study9s power for assessing gene-gene interactions. Larger studies are clearly warranted to further test racial/ethnic specific DNA-repair nsSNPs in human colon and prostate cancer risk. Future studies will also focus on racial/ethnic-specific gene-environment interactions (e.g., DNA damage/repair and smoking history, dietary folate intake, selenium, lycopene, or vitamins D/E) in cancer risk and progression. Since genotypes are not modifiable, this approach aims to identify race-specific environmental risk factors and DNA damage/repair functional markers so that we can motivate and educate genetically susceptible (sub)populations to seek screening and other procedures to prevent tumor development and progression. (Supported by National Institute of Health, R01 CA66635, RO1 CA90898, and P30 DK34987; American Cancer Society, CNE-101119).