Effects of base excision repair gene polymorphisms on pancreatic cancer survival

Abstract

To explore the association between single nucleotide polymorphisms of DNA repair genes and overall survival of patients with pancreatic cancer, we conducted a study in 378 cases of pancreatic adenocarcinoma who were treated at The University of Texas M. D. Anderson Cancer Center between February 1999 and October 2004 and were followed up to April 2006. Genotypes were determined using genomic DNA and the MassCode method. Overall survival was analyzed using the Kaplan-Meier plot, log-rank test and Cox regression. We observed a strong effect of the POLB A165G and T2133C genotypes on overall survival. The median survival time (MST) was 35.7 months for patients carrying at least 1 of the 2 homozygous variant POLB GG or CC genotypes, compared with 14.8 months for those carrying the AA/AG or TT/TC genotypes (p = 0.02, log rank test). The homozygous variants of hOGG1 G2657A, APEX1 D148E and XRCC1 R194W polymorphisms all showed a weak but significant effect on overall survival as demonstrated by either log rank test or multivariate COX regression after adjusting for other potential confounders. In combined genotype analysis, a predominant effect of the POLB homozygous variants on survival was observed. When POLB was not included in the model, a slightly better survival was observed among those carrying none of the adverse genotypes than those carrying at least one of the adverse genotypes. These observations suggest that polymorphisms of base excision repair genes significantly affect the clinical outcome of patients with pancreatic cancer. These observations need to be confirmed in a larger study of homogenous patient population.

FIGURE 1

Survival plots for all patients by genotype of POLB A165G (A), POLB T2133C (B), hOGG1 G2657A (D) and hOGG1 C326G (E). Panels C and F are combined genotypes of the 2 SNPs for POLB and hOGG1, respectively. The numbers 0 and ≥1 in panels C and F indicate the number of variant alleles that are associated with significantly increased or reduced survivals. For example, in panel C, 0 indicates having POLB 165 AA/AG and 2133 TT/TC genotypes and ≥1 indicates having at least 1 of the 2 variant alleles of 165 GG and 2133 CC. In panel F, 0 indicates having hOGG1 2657GG/ GA, and 326 CC/CG genotypes and ≥1 indicates having at least 1 of the 2 variant alleles of 2657AA and 326GG. P values from log rank test, hazard ratios, and 95% confidence intervals are shown in Table IV. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

FIGURE 2

Combined genotype effects on overall survival. The numbers 0–3 indicate the number of variant alleles that are associated with significantly reduced survivals. For example, 0 indicates having none of the POLB 165 AG/AA or 2133 TC/CC, hOGG1 2657AA or 326 GG, APEX1 D148E GG and XRCC1 R194W TT genotypes and 1 indicates having at least 1 of the these variant alleles. P values are from log rank test. The hazard ratio (95% confidence interval) is 4.35 (1.74–10.9), 6.45 (2.55–16.4) and 4.25 (1.51–11.9) for patients carrying 1, 2 or 3 adverse genotypes, respectively, with adjustment of race and other clinical factors. Lower panel excluded the POLB gene but included XRCC1 Q399R AG/GG and LIG4 TT as the additional adverse genotypes. The adjusted hazard ratio (95% confidence interval) is 1.53 (1.05–2.24), 1.65 (1.08–2.52) and 1.60 (0.83–3.07), respectively, for those carrying 1, 2 or 3 adverse genotypes. [Color figure can be viewed in the online issue, which is available at www. interscience.wiley.com.]