The Prostate TheHomozygous P582SMutation inthe Oxygen-DependentDegradationDomainofHIF-1ais AssociatedWith IncreasedRisk for ProstateCancer

BACKGROUND. The heterodimeric transcription factor HIF-1 (hypoxia-inducible factor 1), consisting of a critically regulated HIF-1a subunit and a constitutively expressed HIF-1b subunit, is a master regulator of genes involved in adaptation and survival under low-oxygen conditions. Increased levels of HIF-1 activity are associated with increased tumor aggressiveness, therapeutic resistance, and mortality. METHODS. We studied 402 prostate cancer patients for the presence of the 1772C>T (P582S) and 1790G>A (A588T) mutations within the oxygen-dependent domain of HIF-1a. RESULTS. Homozygosity for the P582Smutation was fourfold greater among prostate cancer patients compared to controls (OR1⁄4 4.10 [C.I. 95% 1.11<OR< 17.87], P1⁄4 0.018). The existence of this mutation in prostate cancer patients was not associated with any of the clinical or pathological characteristics of the disease. No significant differences were found between the frequencies of A588T mutation in prostate cancer patients and controls. CONCLUSIONS. Our data suggest that homozygous HIF1A P582S mutation confers significant susceptibility to prostate cancer. Prostate # 2006 Wiley-Liss, Inc.