Dataset Information

Individual and cumulative effect of prostate cancer risk-associated variants on clinicopathologic variables in 5,895 prostate cancer patients.

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.

SUBMITTER: Kader AK

PROVIDER: S-EPMC2852875 | biostudies-literature | 2009 Aug

REPOSITORIES: biostudies-literature

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Individual and cumulative effect of prostate cancer risk-associated variants on clinicopathologic variables in 5,895 prostate cancer patients.

Kader A Karim AK Sun Jielin J Isaacs Sarah D SD Wiley Kathleen E KE Yan Guifang G Kim Seong-Tae ST Fedor Helen H DeMarzo Angelo M AM Epstein Jonathan I JI Walsh Patrick C PC Partin Alan W AW Trock Bruce B Zheng S Lilly SL Xu Jianfeng J Isaacs William W

The Prostate 20090801 11

<h4>Background</h4>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.<h4>Methods</h4>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 sa ...[more]

PMID: 19434657

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Project description:Active surveillance (AS) is an important strategy to reduce prostate cancer overtreatment. However, the optimal criteria for eligibility and predictors of progression while on AS are debated.To review primary data on markers, genetic factors, and risk stratification for patient selection and predictors of progression during AS.Electronic searches were conducted in PubMed, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) from inception to April 2014 for original articles on biomarkers and risk stratification for AS.Patient factors associated with AS outcomes in some studies include age, race, and family history. Multiple studies provide consistent evidence that a lower percentage of free prostate-specific antigen (PSA), a higher Prostate Health Index (PHI), a higher PSA density (PSAD), and greater biopsy core involvement at baseline predict a greater risk of progression. During follow-up, serial measurements of PHI and PSAD, as well as repeat biopsy results, predict later biopsy progression. While some studies have suggested a univariate relationship between urinary prostate cancer antigen 3 (PCA3) and transmembrane protease, serine 2-v-ets avian erythroblastosis virus E26 oncogene homolog gene fusion (TMPRSS2:ERG) with adverse biopsy features, these markers have not been consistently shown to independently predict AS outcomes. No conclusive data support the use of genetic tests in AS. Limitations of these studies include heterogeneous definitions of progression and limited follow-up.There is a growing body of literature on patient characteristics, biopsy features, and biomarkers with potential utility in AS. More data are needed on practical applications such as combining these tests into multivariable clinical algorithms and long-term outcomes to further improve AS in the future.Several PSA-based tests (free PSA, PHI, PSAD) and the extent of cancer on biopsy can help to stratify the risk of progression during active surveillance. Investigation of several other markers is under way.

Project description:AimTo assess the individual and combined effect of 46 type 2 diabetes related risk alleles on incidence of a composite CVD endpoint.MethodsData from the first Danish MONICA study (N = 3523) and the Inter99 study (N = 6049) was used. Using Cox proportional hazard regression the individual effect of each risk allele on incident CVD was analyzed. Risk was presented as hazard ratios (HR) per risk allele.ResultsDuring 80,859 person years 1441 incident cases of CVD (fatal and non-fatal) occurred in the MONICA study. In Inter99 942 incident cases were observed during 61,239 person years. In the Danish MONICA study four gene variants were significantly associated with incident CVD independently of known diabetes status at baseline; SLC2A2 rs11920090 (HR 1.147, 95% CI 1.027-1.283 , P = 0.0154), C2CD4A rs7172432 (1.112, 1.027-1.205 , P = 0.0089), GCKR rs780094 (1.094, 1.007-1.188 , P = 0.0335) and C2CD4B rs11071657 (1.092, 1.007-1.183 , P = 0.0323). The genetic score was significantly associated with increased risk of CVD (1.025, 1.010-1.041, P = 0.0016). In Inter99 two gene variants were associated with risk of CVD independently of diabetes; SLC2A2 (HR 1.180, 95% CI 1.038-1.341 P = 0.0116) and FTO (0.909, 0.827-0.998, P = 0.0463). Analysing the two populations together we found SLC2A2 rs11920090 (HR 1.164, 95% CI 1.070-1.267, P = 0.0004) meeting the Bonferroni corrected threshold for significance. GCKR rs780094 (1.076, 1.010-1.146, P = 0.0229), C2CD4B rs11071657 (1.067, 1.003-1.135, P = 0.0385) and NOTCH2 rs10923931 (1.104 (1.001 ; 1.217 , P = 0.0481) were found associated with CVD without meeting the corrected threshold. The genetic score was significantly associated with increased risk of CVD (1.018, 1.006-1.031, P = 0.0043).ConclusionsThis study showed that out of the 46 genetic variants examined only the minor risk allele of SLC2A2 rs11920090 was significantly (P = 0.0005) associated with a composite endpoint of incident CVD below the threshold for statistical significance corrected for multiple testing. This potential pathway needs further exploration.

Dataset Information

Individual and cumulative effect of prostate cancer risk-associated variants on clinicopathologic variables in 5,895 prostate cancer patients.

Publications

Individual and cumulative effect of prostate cancer risk-associated variants on clinicopathologic variables in 5,895 prostate cancer patients.

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