Hypoxia-inducible factor-1alpha polymorphisms are associated with genetic aberrations in lung cancer.

摘要

BACKGROUND AND 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-1alpha variants, C1772T (P582S) and G1790A (A588T), which are known to enhance transcriptional activity, were evaluated in lung cancers. METHODS: HIF-1alpha 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-1alpha gene may have an important impact on lung carcinogenesis, especially in adenocarcinomas, possibly by increasing genomic instability.