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Genome-wide association study identifies a genetic variant associated with risk for more aggressive prostate cancer.

ABSTRACT: Of the 200,000 U.S. men annually diagnosed with prostate cancer, approximately 20% to 30% will have clinically aggressive disease. Although factors such as Gleason score and tumor stage are used to assess prognosis, there are no biomarkers to identify men at greater risk for developing aggressive prostate cancer. We therefore undertook a search for genetic variants associated with risk of more aggressive disease.A genome-wide scan was conducted in 202 prostate cancer cases with a more aggressive phenotype and 100 randomly sampled, age-matched prostate-specific antigen screened negative controls. Analysis of 387,384 autosomal single nucleotide polymorphisms (SNPs) was followed by validation testing in an independent set of 527 cases with more aggressive and 595 cases with less aggressive prostate cancer, and 1,167 age-matched controls.A variant on 15q13, rs6497287, was confirmed to be most strongly associated with more aggressive (P(discovery) = 5.20 × 10(-5), P(validation) = 0.004) than less aggressive disease (P = 0.14). Another SNP on 3q26, rs3774315, was found to be associated with prostate cancer risk; however, the association was not stronger for more aggressive disease.This study provides suggestive evidence for a genetic predisposition to more aggressive prostate cancer and highlights the fact that larger studies are warranted to confirm this supposition and identify further risk variants.These findings raise the possibility that assessment of genetic variation may one day be useful to discern men at higher risk for developing clinically significant prostate cancer.

SUBMITTER: FitzGerald LM

PROVIDER: S-EPMC3111761 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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Genome-wide association study identifies a genetic variant associated with risk for more aggressive prostate cancer.

FitzGerald Liesel M LM Kwon Erika M EM Conomos Matthew P MP Kolb Suzanne S Holt Sarah K SK Levine David D Feng Ziding Z Ostrander Elaine A EA Stanford Janet L JL

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20110405 6

<h4>Background</h4>Of the 200,000 U.S. men annually diagnosed with prostate cancer, approximately 20% to 30% will have clinically aggressive disease. Although factors such as Gleason score and tumor stage are used to assess prognosis, there are no biomarkers to identify men at greater risk for developing aggressive prostate cancer. We therefore undertook a search for genetic variants associated with risk of more aggressive disease.<h4>Methods</h4>A genome-wide scan was conducted in 202 prostate ...[more]

PMID: 21467234

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Project description:BackgroundHuman and animal prion diseases are under genetic control, but apart from PRNP (the gene that encodes the prion protein), we understand little about human susceptibility to bovine spongiform encephalopathy (BSE) prions, the causal agent of variant Creutzfeldt-Jakob disease (vCJD).MethodsWe did a genome-wide association study of the risk of vCJD and tested for replication of our findings in samples from many categories of human prion disease (929 samples) and control samples from the UK and Papua New Guinea (4254 samples), including controls in the UK who were genotyped by the Wellcome Trust Case Control Consortium. We also did follow-up analyses of the genetic control of the clinical phenotype of prion disease and analysed candidate gene expression in a mouse cellular model of prion infection.FindingsThe PRNP locus was strongly associated with risk across several markers and all categories of prion disease (best single SNP [single nucleotide polymorphism] association in vCJD p=2.5 x 10(-17); best haplotypic association in vCJD p=1 x 10(-24)). Although the main contribution to disease risk was conferred by PRNP polymorphic codon 129, another nearby SNP conferred increased risk of vCJD. In addition to PRNP, one technically validated SNP association upstream of RARB (the gene that encodes retinoic acid receptor beta) had nominal genome-wide significance (p=1.9 x 10(-7)). A similar association was found in a small sample of patients with iatrogenic CJD (p=0.030) but not in patients with sporadic CJD (sCJD) or kuru. In cultured cells, retinoic acid regulates the expression of the prion protein. We found an association with acquired prion disease, including vCJD (p=5.6 x 10(-5)), kuru incubation time (p=0.017), and resistance to kuru (p=2.5 x 10(-4)), in a region upstream of STMN2 (the gene that encodes SCG10). The risk genotype was not associated with sCJD but conferred an earlier age of onset. Furthermore, expression of Stmn2 was reduced 30-fold post-infection in a mouse cellular model of prion disease.InterpretationThe polymorphic codon 129 of PRNP was the main genetic risk factor for vCJD; however, additional candidate loci have been identified, which justifies functional analyses of these biological pathways in prion disease.

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Genome-wide association study identifies a genetic variant associated with risk for more aggressive prostate cancer.

Publications

Genome-wide association study identifies a genetic variant associated with risk for more aggressive prostate cancer.

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