Abstract 898: Glucose metabolism Gene Polymorphisms and Clinical Outcome in Pancreatic Cancer

Abstract

Abstract Background Altered glucose-metabolism is the most common metabolic hallmark of malignancies. The ‘Warburg effect’ (aerobic glycolysis, a persistently high rate of glucose conversion into lactate even under normoxic condition), is a distinctive metabolic characteristic of malignancies that distinguishes them from normal cells. Glucose-metabolism plays a crucial role in determining the cell fate (survival or death), has become a therapeutic target for cancer treatment. We explored weather glucose-metabolism gene variations correlate with clinical outcome in pancreatic cancer. Methods We retrospectively genotyped 26 single nucleotide polymorphisms (SNPs) from 5 glucose-metabolism genes (Hexokinase 2,HK2; glucokinase, GCK; glutamine-fructose-6-phosphate transaminase, GFPT1; glucose phosphate isomerase, GPI; O-linked N-acetylglucosamine (GlcNAc) transferase, OGT) in 154 patients with localized disease enrolled in clinical trials of preoperative gemcitabine-based chemoradiation and validated the findings in 552 patients with different stages of pancreatic adenocarcinoma recruited in a case-control study conducted at The University of Texas M. D. Anderson Cancer Center from February 1999 to May 2007, with follow-up to August 2009. Association between genotypes and overall survival (OS) or tumor characteristics was evaluated using multivariable Cox proportional hazard regression or logistic regression models with adjustment of clinical predictors. Findings GCK IVS1+9652C>T and HK2 N692N homozygous variants were significantly associated with reduced OS in the training set of 154 patients (P < 0.001). These associations were confirmed in the validation set of 552 patients and in the combined dataset of all 706 patients (Ps ≤ 0.001). In addition, HK2 R844K variant K allele was associated with a better survival in the validation set and the combined dataset (Ps ≤ 0.001). When data was further analyzed by disease stage, GFPT1 IVS14-3094T>C, HK2 N692N and R844K in patients with localized disease, and GCK IVS1+9652C>T in patients with advanced disease were significant independent predictors for OS (Ps ≤ 0.001). Haplotype CGG of GPI and GCTATGG of HK2 were associated with better OS, respectively, with a P value of 0.004 and 0.007. HK2 N692N CC, R844K GG genotype correlated with poorer tumor response to therapy, advanced tumor stage and lower rate of tumor resectability. Interpretation We demonstrated that glucose-metabolism gene polymorphisms correlated with clinical outcome in pancreatic cancer. If confirmed, the genotype marker may be useful in identifying patients for glucose-metabolism-targeted therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 898.