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

Federico Innocenti, Kouros Owzar, Nancy L. Cox, Patrick Evans, Michiaki Kubo, Hitoshi Zembutsu, Chen Jiang, Donna Hollis, Taisei Mushiroda, Liang Li, Paula Friedman, Liewei Wang, Dylan Glubb, Herbert Hurwitz, Kathleen M. Giacomini, Howard L. McLeod, Richard M. Goldberg, Richard L. Schilsky, Hedy L. Kindler, Yusuke NakamuraMark J. Ratain

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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: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.

Original languageEnglish
Pages (from-to)577-584
Number of pages8
JournalClinical Cancer Research
Volume18
Issue number2
DOIs
Publication statusPublished - 15-01-2012

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gemcitabine
Genome-Wide Association Study
Pancreatic Neoplasms
Interleukin-17
Survival
Single Nucleotide Polymorphism
Confidence Intervals
DNA
Linkage Disequilibrium
Heterozygote
Proportional Hazards Models
Neoplasms
Leukemia
Research Design
Placebos
Genome

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Innocenti, Federico ; Owzar, Kouros ; Cox, Nancy L. ; Evans, Patrick ; Kubo, Michiaki ; Zembutsu, Hitoshi ; Jiang, Chen ; Hollis, Donna ; Mushiroda, Taisei ; Li, Liang ; Friedman, Paula ; Wang, Liewei ; Glubb, Dylan ; Hurwitz, Herbert ; Giacomini, Kathleen M. ; McLeod, Howard L. ; Goldberg, Richard M. ; Schilsky, Richard L. ; Kindler, Hedy L. ; Nakamura, Yusuke ; Ratain, Mark J. / A genome-wide association study of overall survival in pancreatic cancer patients treated with gemcitabine in CALGB 80303. In: Clinical Cancer Research. 2012 ; Vol. 18, No. 2. pp. 577-584.
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title = "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: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.",
author = "Federico Innocenti and Kouros Owzar and Cox, {Nancy L.} and Patrick Evans and Michiaki Kubo and Hitoshi Zembutsu and Chen Jiang and Donna Hollis and Taisei Mushiroda and Liang Li and Paula Friedman and Liewei Wang and Dylan Glubb and Herbert Hurwitz and Giacomini, {Kathleen M.} and McLeod, {Howard L.} and Goldberg, {Richard M.} and Schilsky, {Richard L.} and Kindler, {Hedy L.} and Yusuke Nakamura and Ratain, {Mark J.}",
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Innocenti, F, Owzar, K, Cox, NL, Evans, P, Kubo, M, Zembutsu, H, Jiang, C, Hollis, D, Mushiroda, T, Li, L, Friedman, P, Wang, L, Glubb, D, Hurwitz, H, Giacomini, KM, McLeod, HL, Goldberg, RM, Schilsky, RL, Kindler, HL, Nakamura, Y & Ratain, MJ 2012, 'A genome-wide association study of overall survival in pancreatic cancer patients treated with gemcitabine in CALGB 80303', Clinical Cancer Research, vol. 18, no. 2, pp. 577-584. https://doi.org/10.1158/1078-0432.CCR-11-1387

A genome-wide association study of overall survival in pancreatic cancer patients treated with gemcitabine in CALGB 80303. / Innocenti, Federico; Owzar, Kouros; Cox, Nancy L.; Evans, Patrick; Kubo, Michiaki; Zembutsu, Hitoshi; Jiang, Chen; Hollis, Donna; Mushiroda, Taisei; Li, Liang; Friedman, Paula; Wang, Liewei; Glubb, Dylan; Hurwitz, Herbert; Giacomini, Kathleen M.; McLeod, Howard L.; Goldberg, Richard M.; Schilsky, Richard L.; Kindler, Hedy L.; Nakamura, Yusuke; Ratain, Mark J.

In: Clinical Cancer Research, Vol. 18, No. 2, 15.01.2012, p. 577-584.

Research output: Contribution to journalArticle

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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