Susceptibility loci associated with prostate cancer progression and mortality.

Abstract

Purpose-Prostate cancer is a heterogenous disease with a variable natural history that is not accurately predicted by currently used prognostic tools.Experimental Design-We genotyped 798 prostate cancer cases of Ashkenazi Jewish ancestry treated for localized prostate cancer between June 1988 and December 2007. Blood samples were prospectively collected and de-identified before being genotyped and matched to clinical data. The survival analysis was adjusted for Gleason score and PSA. We investigated associations between 29 single nucleotide polymorphisms (SNPs) and biochemical recurrence, castration-resistant metastasis, and prostate cancer-specific survival. Subsequently, we performed an independent analysis using a high resolution panel of 13 SNPs.Results-On univariate analysis, 2 SNPs were associated (p<0.05) with biochemical recurrence; 3 SNPs were associated with clinical metastases; and 1 SNP was associated with prostate cancerspecific mortality. Applying a Bonferroni correction (p<0.0017), one association with biochemical recurrence (p=0.0007) was significant. Three SNPs showed associations on multivariable analysis, although not after correcting for multiple testing. The secondary analysis identified an additional association with prostate cancer-specific mortality in KLK3 (p<0.0005 by both univariate and multivariable analysis).Conclusions-We identified associations between prostate cancer susceptibility SNPs and clinical endpoints. The rs61752561 in KLK3 and rs2735839 in the KLK2-KLK3 intergenic region associated strongly with prostate cancer-specific survival, and rs10486567 in 7JAZF1 gene associated with biochemical recurrence. A larger study will be required to independently validate these findings and determine the role of these SNPs in prognostic models.

Prostate cancer: germline prediction for a commonly variable malignancy

“…One study reported an association between rs7920517, rs10993994 and PSA recurrence after prostatectomy, and others have identifi ed germline predictors of biochemical recurrence, development of castrate-resistance metastases and prostate cancer specifi c mortality, but in general this is an area which would benefi t greatly from further research [ 58,59 ] .…”

Steroidogenic Germline Polymorphism Predictors of Prostate Cancer Progression in the Estradiol Pathway

“…Another useful and much simpler approach to predict prostate cancer outcomes relies on identifying key inherited genetic variations involved in disease progression (4,5). In fact, potential molecular determinants of clinical outcomes have been identified as components encoded by immune system genes (6, 7), sex steroid-related genes (4,8), and, with conflicting results, prostate cancer risk alleles (9)(10)(11)(12). The importance of studying host steroidogenic pathways comes from observations that prostate cells possess the enzymatic machinery for intracrine conversion of precursors into more potent Authors' Affiliations:…”

Genetic variants in the TEP1 gene are associated with prostate cancer risk and recurrence

“…4 Germline variation has been associated with risk of PCa and the recent use of genetic information to predict outcome and to guide treatment has also been steadily increasing in oncologic research and practice. 5 Telomeres are terminal, tandem nucleotide repeats (5′-TTAGGG-3′), in complex with telomere-binding proteins located at the ends of every chromosome, and are key components in the maintenance of chromosomal stability. 6,7 In somatic cells, telomeres are shortening by 30-200 base pairs after each mitotic division due to the end-replication problem.…”

“…39 Given the potential genetic heterogeneity existing in tumor tissues, the use of inherited variation to predict treatment response is appealing, which could potentially allow for more tailored PCa therapies. Several SNPs have yet been identified, which adds clinically significant increment to the prognostic power of currently used clinical indicators and seem to improve the predictive accuracy of preoperative nomograms for tumor progression.…”

“…Several SNPs have yet been identified, which adds clinically significant increment to the prognostic power of currently used clinical indicators and seem to improve the predictive accuracy of preoperative nomograms for tumor progression. 39,40 As initial studies investigating prognostic endpoints were inconsistent, 39,41,42 we chose the clinical endpoint of BCR when designing the study. Although BCR itself portends a variable prognosis and does not always predict systemic recurrence, 3 its use as a primary outcome after RP is significant, because BCR is the primary trigger for further intervention with salvage radiation therapy or androgen-deprivation therapy.…”