Heritable interleukin-17F (IL17F) gene variation and overall survival (OS) in pancreatic cancer patients (pts): Results from a genome-wide association study (GWAS) in CALGB 80303

Abstract

4531Background: CALGB 80303 was a randomized, phase III study in 602 advanced pancreatic cancer (PC) pts treated with gemcitabine plus either bevacizumab or placebo. No difference in OS was observed between the two arms (Kindler, ASCO 2007). As part of the study, we prospectively collected germline DNA for pharmacogenetic studies, originally focusing on the association of candidate genes with OS and toxicity. We subsequently amended the study to conduct a GWAS in order to identify other associations. Methods: Germline DNA was isolated from peripheral blood on 352 pts, and was typed for more than 550,000 SNPs using the Illumina550 platform. The associations between OS and SNPs were investigated using the log-rank test. A review of the clinical data and ancestry genomic analysis identified 294 pts who were clinically eligible and determined to be genetically European, and this subset was used for the primary analysis. Results: For the analysis of OS, pts in both arms were pooled, and two SNPs were associated with OS using genome-wide criteria (p≤10–7). This included an intergenic SNP on chromosome 15 (rs7174643), and a nonsynonymous SNP in the IL17F gene ( rs763780 ) with an allelic frequency of 3.9% (H161R, p<2.7x10–8). Median OS was significantly shorter for the H/R heterozygotes (3.1 months, 95% CI 2.3–4.3, n=23), as compared to the H/H homozygotes (6.8 months, 95% CI 5.8–7.3, n=271). This association remained highly significant when the analysis was stratified by extent of disease or previous radiotherapy. There was no evidence of an interaction with bevacizumab, suggesting that this SNP is prognostic rather than predictive. Conclusions: Heritable variation in IL17F may be a prognostic marker for PC. Wildtype (161H) IL17F is a pro-inflammatory, anti-angiogenic cytokine (Starnes, J Immunol 2001). The 161R mutant IL17F antagonizes wildtype IL17F (Kawaguchi, J Allergy Clin Immunol, 2006), potentially resulting in a pro-angiogenic effect. Replication studies in PC and other solid tumors are indicated.[Table: see text]