title: Validation of genetic sequence variants as prognostic factors in early-stage head and neck squamous cell cancer survival.
abstract: OBJECTIVE
  From the published literature, we identified 23 germ line sequence variants in 17 genes from hypothesis-generating studies that were associated with prognosis of head and neck cancer, including sequence variants of DNA repair (ERCC1, ERCC4, ERCC5, MSH2, XPA, ERCC2, XRCC1, XRCC3), DNA methylation (DNMT3B), cell cycle and proliferation (CCND1, TP53), xenobiotic metabolism (GSTM1, GSTT1, CYP2D6), metastatic -potential (MMP3), immunologic (CTLA4), and growth factor pathways (FGFR4). The purpose of this study was to validate the role of these 23 sequence variants for overall (OS) and disease-free survival (DFS) in a large, comprehensive, well-annotated data set of patients with head and neck cancer.
  
  
  METHODS
  We genotyped these sequence variants in 531 patients with stage I and II radiation-treated head and neck cancer (originally recruited for an alpha-tocopherol/beta-carotene placebo-controlled secondary prevention study), and analyzed using Cox proportional hazards models, stratified by treatment arm, adjusting for clinical prognostic factors.
  
  
  RESULTS
  Two OS associations were statistically significant for each variant allele when compared with the wild-type: CTLA4: A49G [rs231775; adjusted HR (aHR), 1.32 (1.1-1.6); P = 0.01] and XRCC1: Arg339Gln [rs25487; aHR, 1.28 (1.05-1.57); P = 0.02]. Both of these sequence variants had significant results in the opposite direction as prior published literature. Two DFS associations were of borderline significance in the same direction as prior literature: ERCC2: Lys751Gln [rs13181; aHR, 0.80 (0.6-1.0); P = 0.05] and TP53: Arg72Pro [rs1042522; aHR, 1.28 (1.0-1.6); P = 0.03], comparing number of variant alleles with reference of zero variants.
  
  
  CONCLUSIONS
  None of the prognostic sequence variants previously published was validated for OS in our patients with early-stage radiation-treated head and neck cancer, though rs1381and rs1042522 had borderline significant association with DFS.
authors.affiliation: Applied Molecular Oncology, Ontario Cancer Institute, Princess Margaret Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Abul Kalam
authors.initials: AK
authors.lastname: Azad
authors.forename: Isabelle
authors.initials: I
authors.lastname: Bairati
authors.forename: Elodie
authors.initials: E
authors.lastname: Samson
authors.forename: Dangxiao
authors.initials: D
authors.lastname: Cheng
authors.forename: Maryam
authors.initials: M
authors.lastname: Mirshams
authors.forename: Xin
authors.initials: X
authors.lastname: Qiu
authors.forename: Sevtap
authors.initials: S
authors.lastname: Savas
authors.forename: John
authors.initials: J
authors.lastname: Waldron
authors.forename: Changshu
authors.initials: C
authors.lastname: Wang
authors.forename: David
authors.initials: D
authors.lastname: Goldstein
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.forename: Francois
authors.initials: F
authors.lastname: Meyer
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Liu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000401:mortality* / Q000532:radiotherapy; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000532:radiotherapy; D006801:Humans; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm