title: A genome-wide association study of overall survival in pancreatic cancer patients treated with gemcitabine in CALGB 80303.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Department of Medicine, Cancer and Leukemia Group B (CALGB), University of Chicago, Chicago, Illinois, USA.
authors.forename: Federico
authors.initials: F
authors.lastname: Innocenti
authors.forename: Kouros
authors.initials: K
authors.lastname: Owzar
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Cox
authors.forename: Patrick
authors.initials: P
authors.lastname: Evans
authors.forename: Michiaki
authors.initials: M
authors.lastname: Kubo
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Zembutsu
authors.forename: Chen
authors.initials: C
authors.lastname: Jiang
authors.forename: Donna
authors.initials: D
authors.lastname: Hollis
authors.forename: Taisei
authors.initials: T
authors.lastname: Mushiroda
authors.forename: Liang
authors.initials: L
authors.lastname: Li
authors.forename: Paula
authors.initials: P
authors.lastname: Friedman
authors.forename: Liewei
authors.initials: L
authors.lastname: Wang
authors.forename: Dylan
authors.initials: D
authors.lastname: Glubb
authors.forename: Herbert
authors.initials: H
authors.lastname: Hurwitz
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Giacomini
authors.forename: Howard L
authors.initials: HL
authors.lastname: McLeod
authors.forename: Richard M
authors.initials: RM
authors.lastname: Goldberg
authors.forename: Richard L
authors.initials: RL
authors.lastname: Schilsky
authors.forename: Hedy L
authors.initials: HL
authors.lastname: Kindler
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Ratain
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D000368:Aged; D019943:Amino Acid Substitution; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D017326:Clinical Trials, Phase III as Topic; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004311:Double-Blind Method; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D020381:Interleukin-17 / Q000235:genetics*; D053208:Kaplan-Meier Estimate; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D020641:Polymorphism, Single Nucleotide; D016032:Randomized Controlled Trials as Topic; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; C440021:IL17F protein, human; D020381:Interleukin-17; D003841:Deoxycytidine; D000093542:Gemcitabine