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Genetic correction of PSA values using sequence variants associated with PSA levels.

ABSTRACT: Measuring serum levels of the prostate-specific antigen (PSA) is the most common screening method for prostate cancer. However, PSA levels are affected by a number of factors apart from neoplasia. Notably, around 40% of the variability of PSA levels in the general population is accounted for by inherited factors, suggesting that it may be possible to improve both sensitivity and specificity by adjusting test results for genetic effects. To search for sequence variants that associate with PSA levels, we performed a genome-wide association study and follow-up analysis using PSA information from 15,757 Icelandic and 454 British men not diagnosed with prostate cancer. Overall, we detected a genome-wide significant association between PSA levels and single-nucleotide polymorphisms (SNPs) at six loci: 5p15.33 (rs2736098), 10q11 (rs10993994), 10q26 (rs10788160), 12q24 (rs11067228), 17q12 (rs4430796), and 19q13.33 [rs17632542 (KLK3: I179T)], each with P(combined) <3 × 10(-10). Among 3834 men who underwent a biopsy of the prostate, the 10q26, 12q24, and 19q13.33 alleles that associate with high PSA levels are associated with higher probability of a negative biopsy (odds ratio between 1.15 and 1.27). Assessment of association between the six loci and prostate cancer risk in 5325 cases and 41,417 controls from Iceland, the Netherlands, Spain, Romania, and the United States showed that the SNPs at 10q26 and 12q24 were exclusively associated with PSA levels, whereas the other four loci also were associated with prostate cancer risk. We propose that a personalized PSA cutoff value, based on genotype, should be used when deciding to perform a prostate biopsy.

SUBMITTER: Gudmundsson J

PROVIDER: S-EPMC3564581 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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Genetic correction of PSA values using sequence variants associated with PSA levels.

Gudmundsson Julius J Besenbacher Soren S Sulem Patrick P Gudbjartsson Daniel F DF Olafsson Isleifur I Arinbjarnarson Sturla S Agnarsson Bjarni A BA Benediktsdottir Kristrun R KR Isaksson Helgi J HJ Kostic Jelena P JP Gudjonsson Sigurjon A SA Stacey Simon N SN Gylfason Arnaldur A Sigurdsson Asgeir A Holm Hilma H Bjornsdottir Unnur S US Eyjolfsson Gudmundur I GI Navarrete Sebastian S Fuertes Fernando F Garcia-Prats Maria D MD Polo Eduardo E Checherita Ionel A IA Jinga Mariana M Badea Paula P Aben Katja K KK Schalken Jack A JA van Oort Inge M IM Sweep Fred C FC Helfand Brian T BT Davis Michael M Donovan Jenny L JL Hamdy Freddie C FC Kristjansson Kristleifur K Gulcher Jeffrey R JR Masson Gisli G Kong Augustine A Catalona William J WJ Mayordomo Jose I JI Geirsson Gudmundur G Einarsson Gudmundur V GV Barkardottir Rosa B RB Jonsson Eirikur E Jinga Viorel V Mates Dana D Kiemeney Lambertus A LA Neal David E DE Thorsteinsdottir Unnur U Rafnar Thorunn T Stefansson Kari K

Science translational medicine 20101201 62

Measuring serum levels of the prostate-specific antigen (PSA) is the most common screening method for prostate cancer. However, PSA levels are affected by a number of factors apart from neoplasia. Notably, around 40% of the variability of PSA levels in the general population is accounted for by inherited factors, suggesting that it may be possible to improve both sensitivity and specificity by adjusting test results for genetic effects. To search for sequence variants that associate with PSA lev ...[more]

PMID: 21160077

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Project description:ObjectiveTo validate six previously identified markers among men at increased risk of prostate cancer (African-American men and those with a family history of prostate cancer) enrolled in the Prostate Cancer Risk Assessment Program (PRAP), a prostate cancer screening study.Patients and methodsEligibility criteria for PRAP include age 35-69 years with a family history of prostate cancer, African-American ethnicity regardless of family history, and known BRCA gene mutations. The genome-wide association study markers assessed included rs2736098 (5p15.33), rs10993994 (10q11), rs10788160 (10q26), rs11067228 (12q24), rs4430796 (17q12) and rs17632542 (19q13.33). Genotyping methods included either the Taqman(®) single nucleotide polymorphism (SNP) genotyping assay (Applied Biosystems, Foster City, CA, USA) or pyrosequencing. Linear regression models were used to evaluate the association between individual markers and log-transformed baseline PSA levels, while adjusting for potential confounders.ResultsA total of 707 participants (37% Caucasian, 63% African-American) with clinical and genotype data were included in the analysis. Rs10788160 (10q26) was strongly associated with PSA levels among Caucasian participants in the high-risk group (P < 0.01), with a 33.2% increase in PSA level with each A-allele carried. Furthermore, rs10993994 (10q11) was found to be associated with PSA level (P = 0.03) in Caucasian men in the high-risk group, with a 15% increase in PSA level with each T-allele carried. A PSA adjustment model based on allele carrier status at rs10788160 and rs10993994 was proposed, specific to high-risk Caucasian men.ConclusionsGenetic variation at 10q may be particularly important in personalizing the interpretation of PSA level for Caucasian men in the high-risk group. Such information may have clinical relevance in shared decision-making and individualized prostate cancer screening strategies for Caucasian men in the high-risk group, although further study is warranted.

Dataset Information

Genetic correction of PSA values using sequence variants associated with PSA levels.

Publications

Genetic correction of PSA values using sequence variants associated with PSA levels.

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