Effects of base excision repair gene polymorphisms on pancreatic cancer survival

Pancreatic cancer is a rapidly fatal malignancy. The prognosis is extremely poor because this disease is usually diagnosed at a late stage and the tumors are highly aggressive and resistant to most treatments.1 Resistance to therapy leads to large individual variation in response to cytotoxic cancer therapies. To improve treatment efficacy, novel strategies are needed to help clinicians select the most suitable treatment regimen for each patient. Recent developments in pharmacogenomics and gene profiling have provided such opportunities.2 Several studies have shown that genetic variations in DNA repair and drug metabolism significantly affect the clinical outcome of patients receiving cytotoxic therapies.3–7 Gemcitabine and radiotherapy are currently the main therapeutic modalities for advanced pancreatic cancer.8 However, it is not clear what factors influence the clinical response to such treatment. Gemcitabine is a potent radiosensitizer.9 Little is known about DNA repair pathways that may alter cytotoxicity or radio-sensitivity with gemcitabine. On the other hand, it is well known that oxidative DNA damage and resulting DNA strand breaks are the most common type of radiation lesions that lead to mammalian cell death.10 The base excision repair (BER) pathway and the DNA strand break repair pathway are the major repair systems that contribute to the processing of oxidative lesions.11,12 In our previous studies we have shown a significant effect of DNA homologous recombination gene polymorphisms on overall survival of patients with pancreatic cancer.13,14 The current study focuses on the BER pathway. Two subpathways of BER have been characterized by in vitro methods and classified according to the length of the repair patch: the short patch pathway repairs single nucleotides and the long patch pathway repairs lesions of 2–10 nucleotides.15 Short patch repair is the primary pathway for the repair of oxidative DNA damages, but long patch repair may occur when components of short patch repair are saturated or missing. The short patch repair process requires a number of enzymes: a DNA glycosylase, such as 8-oxo-guanine DNA glycosylase (hOGG1), removes the damaged base (e.g., 8-oxoguanine); apurinic/apyrimidinic endonuclease I (APEX1) recognizes and cleaves the resulting abasic (AP) site, introducing a single strand break; X-ray repair cross complementing protein 1 (XRCC1) is a scaffold protein that brings polymerase β (POLB) and ligase III (LIG3) together at the site of repair. DNA POLB adds a single nucleotide to the 3′-end of the nicked AP site and removes the resulting 5′-deoxyribose phosphate group, and a DNA LIG3-XRCC1 complex seals the generated nick.16 Polymorphisms of DNA repair genes may be capable of serving as a genetic marker for individual susceptibility to cytotoxic cancer therapy because of the role of DNA repair in protecting cells from DNA damage-mediated death. To test the hypothesis that genetic variations in BER affect clinical response to chemoradiotherapy and thus patient survival, we examined 9 single nucleotide polymorphisms of 6 major genes (hOGG1, APEX1, POLB, XRCC1, LIG3 and LIG4) that are involved in each step of the short patch BER pathway in 378 patients with a diagnosis of pancreatic ductal adenocarcinomas and who were treated at The University of Texas M. D. Anderson Cancer Center between 1999 and 2004. Overall survival was compared between patients with different genotypes.