New variants at 10q26 and 15q21 are associated with aggressive prostate cancer in a genome-wide association study from a prostate biopsy screening cohort.
ABSTRACT To identify and examine polymorphisms of genes associated with aggressive and clinical significant forms of prostate cancer among a screening cohort.
We conducted a genome-wide association study among patients with aggressive forms of prostate cancer and biopsy-proven normal controls ascertained from a prostate cancer screening program. We then examined significant associations of specific polymorphisms among a prostate cancer screened cohort to examine their predictive ability in detecting prostate cancer.
We found significant associations between aggressive prostate cancer and five single nucleotide polymorphisms (SNPs) in the 10q26 (rs10788165, rs10749408, and rs10788165, p value for association 1.3 × 10(-10 ) to 3.2 × 10(-11) ) and 15q21 (rs4775302 and rs1994198, p values for association 3.1 × 10(-8 ) to 8.2 × 10(-9)) regions. Results of a replication study done in 3439 patients undergoing a prostate biopsy, revealed certain combinations of these SNPs to be significantly associated not only with prostate cancer but with aggressive forms of prostate cancer using an established classification criterion for prostate cancer progression (odds ratios for intermediate to high-risk disease 1.8-3.0, p value 0.003-0.001). These SNP combinations were also important clinical predictors for prostate cancer detection based on nomogram analysis that assesses prostate cancer risk.
Five SNPs were found to be associated with aggressive forms of prostate cancer. We demonstrated potential clinical applications of these associations.
Article: Individual and cumulative effect of prostate cancer risk-associated variants on clinicopathologic variables in 5,895 prostate cancer patients.[show abstract] [hide abstract]
ABSTRACT: 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. 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. 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. 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.The Prostate 05/2009; 69(11):1195-205. · 3.48 Impact Factor
[show abstract] [hide abstract]
ABSTRACT: To determine the practice pattern of repeat prostate biopsies to detect prostate cancer, as there is growing evidence to support the recommendation that a repeat prostate biopsy should be taken after an initially negative prostate biopsy, the rate of cancer detection then being approximately 30%. We examined the practice patterns of taking a repeat prostate biopsy after an initial negative biopsy and the predictors for cancer at repeat biopsy among 1536 patients who had an initial prostate biopsy because of an elevated prostate-specific antigen (PSA) level (>4.0 ng/mL) or abnormal digital rectal examination. Of the 1536 men, 712 (46.4%) had cancer detected on the first biopsy; of the remaining 824 with no cancer detected, 268 (32.5%) had a repeat biopsy within a year, and 68 of these (25.4%) had cancer detected. Of the cancers detected at repeat biopsy, 31% were high-grade. Men with abnormal histology (prostatic intraepithelial neoplasia or atypia) had an odds ratio of 3.2 (P < 0.001) for having a repeat biopsy. For men with normal initial prostate histology, those with an initial PSA of 10.0-20.0 and >20.0 ng/mL had an odds ratio of 3.6 and 4.5 (both P < 0.001), respectively, for a repeat prostate biopsy, compared with patients with a PSA of <10.0 ng/mL. However, the PSA level was not predictive of prostate cancer at repeat biopsy, but age and prostate volume were. A third of patients had a repeat biopsy after a negative biopsy. The most important factors influencing whether a patient was to have a repeat biopsy were initial biopsy histology and PSA level. However, the latter was not an important factor for predicting prostate cancer at repeat biopsy.BJU International 01/2005; 94(9):1239-44. · 2.84 Impact Factor