title: Hypoxia-inducible factor-1α polymorphisms are associated with genetic aberrations in lung cancer.
abstract: OBJECTIVE
  The transcription factor, hypoxia-inducible factor-1 (HIF-1), is a master regulator of hypoxia, including repression of DNA repair systems, resulting in genomic instability in cancer cells. The roles of the polymorphic HIF-1α variants, C1772T (P582S) and G1790A (A588T), which are known to enhance transcriptional activity, were evaluated in lung cancers.
  
  
  METHODS
  HIF-1α polymorphisms were assessed by direct sequencing in a total of 83 lung cancer patients (42 adenocarcinomas, 30 squamous cell, four adenosquamous cell and seven small cell lung carcinomas) and in 110 healthy control subjects. The relationship between these polymorphisms and the frequently observed genetic and/or epigenetic aberrations, TP53 loss of heterozygosity (LOH), 1p34 LOH, retinoblastoma-1 (RB1) LOH, p16 inactivation and epidermal growth factor receptor aberrations, was then assessed.
  
  
  RESULTS
  There were no significant differences in genotype frequencies for either C1772T or G1790A between lung cancer patients and healthy controls. However, the frequency of the HIF1A C1772T variant allele was significantly higher in lung cancer patients with TP53 LOH (P = 0.015). Among adenocarcinoma patients, individuals with variant alleles of either polymorphism showed significantly higher frequencies of TP53 LOH (P = 0.047), 1p34 LOH (P = 0.009), or either of these (P = 0.008) in the tumours. The in vitro transcriptional activity of these HIF1A variants in A549 lung cancer cells was significantly greater than that of the wild type under either normoxic or hypoxic conditions, especially for P582S in cells containing mutant p53 (P < 0.0005 and P < 0.005, respectively).
  
  
  CONCLUSIONS
  These findings indicate that functional polymorphisms in the HIF-1α gene may have an important impact on lung carcinogenesis, especially in adenocarcinomas, possibly by increasing genomic instability.
authors: Department of Radiation Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
authors: Andika C
authors: AC
authors: Putra
authors: Keiji
authors: K
authors: Tanimoto
authors: Marina
authors: M
authors: Arifin
authors: Keiko
authors: K
authors: Hiyama
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics*; D000368:Aged; D018196:Carcinoma, Adenosquamous / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D016022:Case-Control Studies; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D042822:Genomic Instability / Q000235:genetics; D005838:Genotype; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics*; D019656:Loss of Heterozygosity / Q000235:genetics; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D011110:Polymorphism, Genetic / Q000235:genetics*; D055752:Small Cell Lung Carcinoma / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016159:Tumor Suppressor Protein p53