title: A genome-wide association study of non-HPV-related head and neck squamous cell carcinoma identifies prognostic genetic sequence variants in the MAP-kinase and hormone pathways.
abstract: Carcinomas of the oral cavity, pharynx and larynx are referred to as head and neck cancers (HNC); together they account for 2-3% of all newly diagnosed cancers in North America. Between 40-50% of HNC are early diagnosed at stages I-II. The 5-year and 10-year relative survival rates are 61% and 50%, respectively. Germline genetic sequence variants (GSV) have become increasingly found to have prognostic implications in a variety of cancers. Identifying these variants may have important clinical and biological implications.
  
  
  
  We conducted a genome-wide association study (GWAS) in 531 Stage I-II radiation-treated HNC patients (originally recruited for α-tocopherol/β-carotene placebo-controlled secondary prevention study) and used a replication cohort of 566 HNC patients of all stages, of mostly non-HPV-related cancers. Survival rates were estimated by the Kaplan-Meier method. Cox proportional hazards models adjusted for potential clinical factors and principal components were used to test for associations between the GSV and overall survival (OS) in these tumors.
  
  
  
  The median follow-up time for OS was 9.21 years (GWAS cohort) and 2.37 years (replication cohort). In both cohorts, CACNA2D1:rs2299187, ESRRG:rs946465 and ESRRG:rs1416612 were each individually significantly associated with survival. In silico analysis of ESRRG:rs946465 identifies that it produces a splice variant in ESRRG. Variant alleles of CACNA2D1:rs2299187 and ESRRG:rs946465 were associated with higher expression of the corresponding protein.
  
  
  
  Putatively functional polymorphisms in the MAP-Kinase and estrogen pathways, identified through GWAS and replicated in an independent dataset were associated with the survival of HNC patients.
authors.affiliation: Ontario Cancer Institute and Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: Abul Kalam
authors.initials: AK
authors.lastname: Azad
authors.affiliation: Laval University Cancer Research Center, Quebec City, QC, Canada.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Bairati
authors.affiliation: Ontario Cancer Institute and Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: Xin
authors.initials: X
authors.lastname: Qiu
authors.affiliation: Ontario Cancer Institute and Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: Hala
authors.initials: H
authors.lastname: Girgis
authors.affiliation: Ontario Cancer Institute and Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: Lu
authors.initials: L
authors.lastname: Cheng
authors.affiliation: Informatics & Biocomputing Platform, Ontario Institute for Cancer Research, Toronto, ON, Canada.
authors.forename: Daryl
authors.initials: D
authors.lastname: Waggott
authors.affiliation: Ontario Cancer Institute and Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: Dangxiao
authors.initials: D
authors.lastname: Cheng
authors.affiliation: Ontario Cancer Institute and Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: Maryam
authors.initials: M
authors.lastname: Mirshams
authors.affiliation: Ontario Cancer Institute and Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: James
authors.initials: J
authors.lastname: Ho
authors.affiliation: Laval University Cancer Research Center, Quebec City, QC, Canada.
authors.forename: André
authors.initials: A
authors.lastname: Fortin
authors.affiliation: Laval University Cancer Research Center, Quebec City, QC, Canada.
authors.forename: Eric
authors.initials: E
authors.lastname: Vigneault
authors.affiliation: Ontario Cancer Institute and Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: Shao-Hui
authors.initials: SH
authors.lastname: Huang
authors.affiliation: Ontario Cancer Institute and Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: Brian
authors.initials: B
authors.lastname: O'Sullivan
authors.affiliation: Ontario Cancer Institute and Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: John
authors.initials: J
authors.lastname: Waldron
authors.affiliation: Informatics & Biocomputing Platform, Ontario Institute for Cancer Research, Toronto, ON, Canada,; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada,; Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON, Canada.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Boutros
authors.affiliation: Ontario Cancer Institute and Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Goldstein
authors.affiliation: Laval University Cancer Research Center, Quebec City, QC, Canada.
authors.forename: Francois
authors.initials: F
authors.lastname: Meyer
authors.affiliation: Ontario Cancer Institute and Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.affiliation: Ontario Cancer Institute and Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada,; Department of Environmental Health, Harvard School of Public Health, Boston, MA, USA. Electronic address: geoffrey.liu@uhn.on.ca.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Liu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D014644:Genetic Variation / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods*; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000401:mortality; D006801:Humans; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics*; D015996:Survival Rate
chemical_list: D038744:Ribosomal Protein S6 Kinases, 90-kDa
keywords: Genetic sequence variant; Head and neck cancer; Overall survival