Individual and cumulative effect of prostate cancer risk-associated variants on clinicopathologic variables in 5,895 prostate cancer patients.
BACKGROUND
More than a dozen single nucleotide polymorphisms (SNPs) have been associated with prostate cancer (PCa) risk from genome-wide association studies (GWAS). Their association with PCa aggressiveness and clinicopathologic variables is inconclusive.


METHODS
Twenty PCa risk SNPs implicated in GWAS and fine mapping studies were evaluated in 5,895 PCa cases treated by radical prostatectomy at Johns Hopkins Hospital, where each tumor was uniformly graded and staged using the same protocol.


RESULTS
For 18 of the 20 SNPs examined, no statistically significant differences (P > 0.05) were observed in risk allele frequencies between patients with more aggressive (Gleason scores > or =4 + 3, or stage > or =T3b, or N+) or less aggressive disease (Gleason scores < or =3 + 4, and stage < or =T2, and N0). For the two SNPs that had significant differences between more and less aggressive disease rs2735839 in KLK3 (P = 8.4 x 10(-7)) and rs10993994 in MSMB (P = 0.046), the alleles that are associated with increased risk for PCa were more frequent in patients with less aggressive disease. Since these SNPs are known to be associated with PSA levels in men without PCa diagnoses, these latter associations may reflect the enrichment of low grade, low stage cases diagnosed by contemporary disease screening with PSA.


CONCLUSIONS
The vast majority of PCa risk-associated SNPs are not associated with aggressiveness and clinicopathologic variables of PCa. Correspondingly, they have minimal utility in predicting the risk for developing more or less aggressive forms of PCa.
Center for Cancer Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.
A Karim
AK
Kader
Jielin
J
Sun
Sarah D
SD
Isaacs
Kathleen E
KE
Wiley
Guifang
G
Yan
Seong-Tae
ST
Kim
Helen
H
Fedor
Angelo M
AM
DeMarzo
Jonathan I
JI
Epstein
Patrick C
PC
Walsh
Alan W
AW
Partin
Bruce
B
Trock
S Lilly
SL
Zheng
Jianfeng
J
Xu
William
W
Isaacs
D014408:Biomarkers, Tumor / Q000097:blood / Q000235:genetics; D015331:Cohort Studies; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011237:Predictive Value of Tests; D017430:Prostate-Specific Antigen / Q000097:blood / Q000235:genetics; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000097:blood / Q000235:genetics* / Q000601:surgery; D029584:Prostatic Secretory Proteins / Q000235:genetics*; D012189:Retrospective Studies; D012307:Risk Factors
D014408:Biomarkers, Tumor; D029584:Prostatic Secretory Proteins; C043076:beta-microseminoprotein; D017430:Prostate-Specific Antigen