Contribution of HPC1 (RNASEL) and HPCX variants to prostate cancer in a founder population.
BACKGROUND
Prostate cancer is a genetically complex disease with locus and disease heterogeneity. The RNASEL gene and HPCX locus have been implicated in hereditary prostate cancer; however, their contributions to sporadic forms of this malignancy remain uncertain.


METHODS
Associations of prostate cancer with two variants in the RNASEL gene (a founder mutation, 471delAAAG, and a non-synonymous SNP, rs486907), and with five microsatellite markers in the HPCX locus, were examined in 979 cases and 1,251 controls of Ashkenazi Jewish descent. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression models.


RESULTS
There was an inverse association between RNASEL rs486907 and prostate cancer in younger men (<65 years) and those with a first-degree relative with prostate cancer; men with AA genotype had ORs of 0.64 and 0.47 (both P < 0.05), respectively, in comparison to men with GG genotype. Within the HPCX region, there were positive associations for allele 135 of bG82i1.1 marker (OR = 1.77, P = 0.01) and allele 188 of DXS1205 (OR = 1.65, P = 0.02). In addition, allele 248 of marker D33 was inversely associated (OR = 0.65, P = 0.05) with Gleason score ≥7 tumors.


CONCLUSIONS
Results suggest that variants in RNASEL contribute to susceptibility to early onset and familial forms of prostate cancer, whereas HPCX variants are associated with prostate cancer risk and tumor aggressiveness. The observation that a mutation predicted to completely inactivate RNASEL protein was not associated with prostate cancer, but that a missense variant was associated, suggests that the effect is due to either partial inactivation of the protein, and/or acquisition of a new protein activity.
Agalliu
Ilir
I
Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Leanza
Suzanne M
SM
Smith
Lorie
L
Trent
Jeffrey M
JM
Carpten
John D
JD
Bailey-Wilson
Joan E
JE
Burk
Robert D
RD
D000230:Adenocarcinoma / Q000235:genetics*; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D004273:DNA, Neoplasm / Q000737:chemistry / Q000235:genetics; D004722:Endoribonucleases / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007585:Jews; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000235:genetics*
D004273:DNA, Neoplasm; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease