DNA Repair Gene Variants Influence Risk for Pancreatic Cancer

Jacquelyn K Beals, PhD

January 21, 2009

January 21, 2009 — Polymorphisms of genes responsible for DNA repair can alter an individual's risk for pancreatic cancer, according to research by scientists at the M.D. Anderson Cancer Center in Houston, Texas. Focusing on variants of DNA repair genes, researchers identified 2 single nucleotide polymorphisms (SNPs) significantly associated with risk for pancreatic cancer: one reduces risk, the other increases it. Interactions between diabetes and genotype were also found to influence pancreatic cancer risk.

Published January 15 in Clinical Cancer Research, the study analyzed 9 SNPs of 7 genes involved in DNA repair processes. These processes include base excision repair, repair of DNA single-strand breaks, and repair of DNA double-strand breaks. Several of the genes investigated had a previously demonstrated association with survival outcomes in pancreatic cancer patients treated with chemoradiation.

The current study enrolled patients with primary pancreatic ductal adenocarcinoma (n = 734) and healthy control patients (n = 780). DNA for genotypes was extracted from peripheral blood. Data on lifestyle variables (cigarette smoking, alcohol consumption, body mass index, and diabetes) were obtained by interview.

Only 2 of the SNPs differed significantly in genotype distribution between patients with primary pancreatic ductal adenocarcinoma and control patients: For the DNA ligase III gene, LIG3 G-39A, the AA mutant genotype was more common in control patients, indicating an association with a lower risk for pancreatic cancer (odds ratio [OR], .23; 95% confidence interval [CI], .06 – .82; P = .024). LIG3 is involved in base excision repair and repair of single-strand breaks in DNA. For the ataxia telangiectasia mutated gene, ATM D1853N, the AA variant genotype was found more frequently among patients with primary pancreatic ductal adenocarcinoma, indicating an association with greater pancreatic cancer risk (OR, 2.55; 95% CI, 1.08 – 6.00; P = .032). The ATM protein helps cells recognize broken or damaged DNA strands.

Interestingly, previous studies have found SNPs of LIG3 to be associated with higher risk for esophageal and some lung cancers, but not breast, colon, bladder, or other lung cancers, lead author Donghui Li, PhD, a professor in the Department of Gastrointestinal Medical Oncology, M.D. Anderson Cancer Center, University of Texas, Houston, explained to Medscape Pathology & Lab Medicine via email.

"The inconsistent observations on genetic associations with cancer are largely related to...study design, [for example], small sample size or mismatched cases and controls. SNPs are common genetic variations that have a low impact on disease susceptibility. The association of a SNP with a disease may be only seen in the presence of certain exposure or other genetic variants," Dr. Li said.

"The functional significance of a polymorphic variant is often unknown," Dr. Li added.. "The observed association of certain SNPs with disease could well be due to linkage of the SNP with other unidentified SNPs or genes that are truly responsible for the disease. So for this type of research, it requires replication in different studies."

The present study also analyzed interactions between the SNPs and factors known to influence pancreatic cancer risk. No significant interactions were found between any of the 9 SNPs and smoking, alcohol consumption, or body mass index. After excluding recent onset diabetes from the analysis, significant interactions were found between diabetes and LIG4 C54T (the gene product repairs broken DNA strands) and between diabetes and ATM D1853N.

The influence of genotype/diabetes interactions on pancreatic cancer risk was apparent in the odds ratios for patients, with or without diabetes, who have the GG genotype of ATM D1853N or the GA/AA genotypes — these confer increased risk and were combined for analysis (P interaction = .032):

  • Nondiabetics with GG genotype — reference group

  • Nondiabetics with GA/AA genotypes (OR, .96; 95% CI, .74 – 1.24)

  • Diabetics with GG genotype (OR, 1.32; 95% CI, .89 – 1.95)

  • Diabetics with GA/AA genotype (OR, 3.23; 95% CI, 1.47 – 7.12).

A similar interaction was observed between LIG4 C54T variants and diabetes (P interaction = .02).

"The interaction of inherited genetic variation and environmental factors is the subject of this and a growing number of reports in the field of pancreatic cancer epidemiology," according to Eric J. Duell, PhD, from the Lifestyle, Environment and Cancer Group, Genetics and Epidemiology Cluster, International Agency for Research on Cancer, World Health Organization, Lyon, France.

He told Medscape Pathology & Lab Medicine via email, "At this stage, it is unlikely that these types of studies will translate into individualized approaches to cancer prediction.... The message we can take from these types of studies is that making healthier lifestyle choices can help to shift the disease burden in the population as a whole," Dr. Duell observed. "These studies can also inform basic research regarding potential carcinogenic mechanisms that may one day translate into better prevention, earlier detection, and more effective treatments."

Dr. Li and Dr. Duell have disclosed no relevant financial relationships.

Clin Cancer Res. 2009;15(2):740–746.

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