TY - JOUR
T1 - A genome-wide association study of overall survival in pancreatic cancer patients treated with gemcitabine in CALGB 80303
AU - Innocenti, Federico
AU - Owzar, Kouros
AU - Cox, Nancy L.
AU - Evans, Patrick
AU - Kubo, Michiaki
AU - Zembutsu, Hitoshi
AU - Jiang, Chen
AU - Hollis, Donna
AU - Mushiroda, Taisei
AU - Li, Liang
AU - Friedman, Paula
AU - Wang, Liewei
AU - Glubb, Dylan
AU - Hurwitz, Herbert
AU - Giacomini, Kathleen M.
AU - McLeod, Howard L.
AU - Goldberg, Richard M.
AU - Schilsky, Richard L.
AU - Kindler, Hedy L.
AU - Nakamura, Yusuke
AU - Ratain, Mark J.
PY - 2012/1/15
Y1 - 2012/1/15
N2 - 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:Anonsynonymous SNPin interleukin (IL)17F (rs763780, H161R) and an intronicSNP 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.
AB - 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:Anonsynonymous SNPin interleukin (IL)17F (rs763780, H161R) and an intronicSNP 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.
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U2 - 10.1158/1078-0432.CCR-11-1387
DO - 10.1158/1078-0432.CCR-11-1387
M3 - Article
C2 - 22142827
AN - SCOPUS:84862908671
SN - 1078-0432
VL - 18
SP - 577
EP - 584
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 2
ER -
