The homozygous P582S mutation in the oxygen-dependent degradation domain of HIF-1 alpha is associated with increased risk for prostate cancer.
BACKGROUND
The heterodimeric transcription factor HIF-1 (hypoxia-inducible factor 1), consisting of a critically regulated HIF-1 alpha subunit and a constitutively expressed HIF-1 beta 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-1 alpha.


RESULTS
Homozygosity for the P582S mutation was fourfold greater among prostate cancer patients compared to controls (OR = 4.10 [C.I. 95% 1.11 < OR < 17.87], P = 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.
Orr-Urtreger
Avi
A
Genetic Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. aviorr@tasmc.health.gov.il
Bar-Shira
Anat
A
Matzkin
Haim
H
Mabjeesh
Nicola J
NJ
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015687:Cell Hypoxia / Q000235:genetics; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000502:physiology; D007585:Jews / Q000235:genetics; D008297:Male; D008875:Middle Aged; D010100:Oxygen / Q000502:physiology*; D017354:Point Mutation / Q000235:genetics*; D011392:Proline / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017434:Protein Structure, Tertiary / Q000235:genetics; D012307:Risk Factors; D012694:Serine / Q000235:genetics
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012694:Serine; D011392:Proline; D010100:Oxygen