A genome-wide association study of overall survival in pancreatic cancer patients treated with gemcitabine in CALGB 80303

Abstract

Background and aims: Cancer and Leukemia Group B 80303 was a randomized, phase III study in patients with advanced pancreatic cancer treated with gemcitabine plus either bevacizumab or placebo. We prospectively collected germline DNA and conducted a genome-wide association study (GWAS) using overall survival (OS) as the endpoint.

Experimental design: DNA from 351 patients was genotyped for more than 550,000 single-nucleotide polymorphisms (SNP). Associations between OS and SNPs were investigated using the log-linear 2-way multiplicative Cox proportional hazards model. The subset of 294 genetically European patients was used for the primary analysis.

Results: A nonsynonymous SNP in interleukin (IL)17F (rs763780, H161R) and an intronic SNP in strong linkage disequilibrium (rs7771466) were associated with OS using genome-wide criteria (P ≤ 10(-7)). Median OS was significantly shorter (P = 2.61 × 10(-8)) for the rs763780 heterozygotes [3.1 months; 95% confidence interval (CI), 2.3-4.3] than for the patients without this variant (6.8 months; 95% CI, 5.8-7.3). After adjustment by stratification factors, the P value for the association was 9.51 × 10(-7).

Conclusions: The variant 161R form of IL-17F is a natural antagonist of the antiangiogenic effects of wild-type 161H IL-17F, and angiogenesis may play an important role in the metastatic spread of pancreatic cancer. In this preliminary study, we hypothesize that the angiogenetic potential of pancreatic cancers in patients with variant IL-17F is higher than that of tumors in patients with wild-type IL-17F, conferring worse prognosis. This exploratory GWAS may provide the foundation for testing the biology and clinical effects of novel genes and their heritable variants through mechanistic and confirmatory studies in pancreatic cancer.

Figure 1. Flow chart of the quality control process in 352 initial patients genotyped with 561,466 SNPs

IBS, identity by state; MAF, minor relative allelic frequency; MGC, minor genotypic counts.

Figure 2. Manhattan plot of SNPs associated with OS in patients of European ancestry with both arms combined

The observed marginal P-values (minus log base 10 scale) are plotted across the chromosomes.

Figure 3. Kaplan-Meier estimate of OS stratified by (A) rs763780 IL17F, (B) rs11644322 WWOX, and (C) rs10883617 BTRC genotypes in patients of European ancestry with both arms combined

For rs763780, A/A, non carriers of rs763780; A/G, heterozygotes. For rs11644322, G/G, non carriers of rs11644322; G/A, heterozygotes; A/A, homozygotes. For rs10883617, A/A, non carriers of rs10883617; A/G, heterozygotes; G/G, homozygotes. The base change is according to the Illumina TOP stranding method for determining strand and allele[33].