title: Examining the polymorphisms in the hypoxia pathway genes in relation to outcome in colorectal cancer.
abstract: BACKGROUND
  Colorectal cancer is a common malignancy. Identification of genetic prognostic markers may help prognostic estimations in colorectal cancer. Genes that regulate response to hypoxia and other genes that are regulated under the hypoxic conditions have been shown to play roles in cancer progression. In this study, we hypothesized that genetic variations in the hypoxia pathway genes were associated with the risk of outcome in colorectal cancer patients.
  
  
  METHODS
  This study was performed in two phases. In the first phase, 49 SNPs from six hypoxia pathway genes (HIF1A, HIF1B, HIF2A, LOX, MIF and CXCL12) in 272 colorectal cancer patients were analyzed. In the second phase, 77 SNPs from seven hypoxia pathway genes (HIF1A, HIF1B, HIF2A, HIF2B, HIF3A, LOX and CXCL12) were analyzed in an additional cohort of 535 patients. Kaplan Meier, Cox univariate and multivariable regression analyses were performed to analyze the relationship between the SNPs and overall survival (OS), disease free survival (DFS) or disease specific survival (DSS). Since this was a hypothesis-generating study, no correction for multiple testing was applied.
  
  
  RESULTS
  In phase I, one SNP (HIF2A rs11125070) was found to be associated with DFS in multivariable analysis; yet association of a proxy polymorphism (HIF2A rs4953342) was not detected in the phase II patient cohort. In phase II, associations of two SNPs (HIF2A rs4953352 and HIF2B rs12593988) were significant in both OS and DFS multivariable analyses. However, association of HIF2A rs4953352 was not replicated in the phase I cohort using a proxy SNP (HIF2A rs6706003).
  
  
  CONCLUSIONS
  Overall, our study did not find a convincing evidence of association of the investigated polymorphisms with the disease outcomes in colorectal cancer.
authors.affiliation: Discipline of Genetics, Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL, Canada.
authors.forename: Asan M S
authors.initials: AM
authors.lastname: Haja Mohideen
authors.affiliation: Discipline of Genetics, Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL, Canada.
authors.forename: Angela
authors.initials: A
authors.lastname: Hyde
authors.affiliation: Discipline of Genetics, Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL, Canada.
authors.forename: Jessica
authors.initials: J
authors.lastname: Squires
authors.affiliation: Division of Community Health and Humanities, Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL, Canada.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Clinical Epidemiology Unit, Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL, Canada.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Dicks
authors.affiliation: Discipline of Genetics, Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL, Canada.
authors.forename: Ban
authors.initials: B
authors.lastname: Younghusband
authors.affiliation: Clinical Epidemiology Unit, Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL, Canada.
authors.forename: Patrick
authors.initials: P
authors.lastname: Parfrey
authors.affiliation: Discipline of Genetics, Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL, Canada.
authors.forename: Roger
authors.initials: R
authors.lastname: Green
authors.affiliation: Discipline of Genetics, Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL, Canada; Discipline of Oncology, Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL, Canada.
authors.forename: Sevtap
authors.initials: S
authors.lastname: Savas
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D051017:Apoptosis Regulatory Proteins; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000235:genetics; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D054377:Chemokine CXCL12 / Q000235:genetics; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D016016:Proportional Hazards Models; D012097:Repressor Proteins; D018570:Risk Assessment / Q000706:statistics & numerical data; D012307:Risk Factors; D015398:Signal Transduction / Q000235:genetics*; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051017:Apoptosis Regulatory Proteins; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D051792:Basic Helix-Loop-Helix Proteins; D054377:Chemokine CXCL12; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012097:Repressor Proteins; D000099162:Endothelial PAS Domain-Containing Protein 1; C497396:ARNT protein, human; C515255:CXCL12 protein, human; C497442:HIF1A protein, human; C116973:HIF3A protein, human