992 GENETIC CORRECTION OF PSA LEVELS AND PROSTATE CANCER RISK MARKERS IMPROVE POSITIVE PREDICTIVE VALUE OF THE PSA TEST (2011)

You have accessJournal of UrologyProstate Cancer: Localized1 Apr 2011992 GENETIC CORRECTION OF PSA LEVELS AND PROSTATE CANCER RISK MARKERS IMPROVE POSITIVE PREDICTIVE VALUE OF THE PSA TEST Julius Gudmundsson, Jeff Gulcher, Soren Besenbacher, Patrick Sulem, Daniel Gudbjartsson, Isleifur Olafsson, Sturla Arinbjarnarson, Bjarni Agnarsson, Kristrun Benediktsdottir, Helgi Isaksson, Unnur Bjornsdottir, Gudmundur Eyjolfsson, Jenny Donovan, Freddie Hamdy, William Catalona, Gudmundur Geirsson, Gudmundur Einarsson, Rosa Barkardottir, Eirikur Jonsson, David Neal, Unnur Thorsteinsdottir, Thorunn Rafnar, and Kari Stefansson Julius GudmundssonJulius Gudmundsson Reykjavik, Iceland More articles by this author , Jeff GulcherJeff Gulcher Reykjavik, Iceland More articles by this author , Soren BesenbacherSoren Besenbacher Reykjavik, Iceland More articles by this author , Patrick SulemPatrick Sulem Reykjavik, Iceland More articles by this author , Daniel GudbjartssonDaniel Gudbjartsson Reykjavik, Iceland More articles by this author , Isleifur OlafssonIsleifur Olafsson Reykjavik, Iceland More articles by this author , Sturla ArinbjarnarsonSturla Arinbjarnarson Reykjavik, Iceland More articles by this author , Bjarni AgnarssonBjarni Agnarsson Reykjavik, Iceland More articles by this author , Kristrun BenediktsdottirKristrun Benediktsdottir Reykjavik, Iceland More articles by this author , Helgi IsakssonHelgi Isaksson Reykjavik, Iceland More articles by this author , Unnur BjornsdottirUnnur Bjornsdottir Reykjavik, Iceland More articles by this author , Gudmundur EyjolfssonGudmundur Eyjolfsson Reykjavik, Iceland More articles by this author , Jenny DonovanJenny Donovan Bristol, United Kingdom More articles by this author , Freddie HamdyFreddie Hamdy Oxford, United Kingdom More articles by this author , William CatalonaWilliam Catalona Chicago, IL More articles by this author , Gudmundur GeirssonGudmundur Geirsson Reykjavik, Iceland More articles by this author , Gudmundur EinarssonGudmundur Einarsson Reykjavik, Iceland More articles by this author , Rosa BarkardottirRosa Barkardottir Reykjavik, Iceland More articles by this author , Eirikur JonssonEirikur Jonsson Reykjavik, Iceland More articles by this author , David NealDavid Neal Cambridge, United Kingdom More articles by this author , Unnur ThorsteinsdottirUnnur Thorsteinsdottir Reykjavik, Iceland More articles by this author , Thorunn RafnarThorunn Rafnar Reykjavik, Iceland More articles by this author , and Kari StefanssonKari Stefansson Reykjavik, Iceland More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.1024AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Inter-individual variability in baseline total prostate specific antigen (PSA) levels has a significant genetic component and accounts, in part, for the limited specificity and sensitivity of the PSA test. Using genetic information to correct the patient‘s PSA level, together with prostate cancer genetic risk estimates, may improve the performance of PSA screening. METHODS To identify genetic variants that associate with baseline PSA levels, we performed a genome-wide association study using PSA information from 9,339 Icelandic men not diagnosed with prostate cancer (PCa) or benign prostatic hyperplasia (BPH) and replicated 6 significant markers in an independent UK study population. We then ran this genetic correction profile using 4 PSA-associated single nucleotide polymorphisms (SNPs) together with a prostate cancer (PCa) genetic risk profile from 23 validated SNPs in 2 large biopsy outcome cohorts totaling 3,994 individuals to test for effect on PCa prediction. RESULTS The markers that showed association to baseline PSA levels did not show association to PCa diagnosed in pre-PSA era or to BPH. These 4 PSA-associated SNPs, in combination, have an effect on PSA levels as high as 1.8 fold and as low as 0.5 fold. In 2 independent prostate biopsy outcome studies, the patient group predicted to have higher baseline levels of PSA, based on these PSA-associated markers, had significantly higher rates of biopsies, in general, and higher rates of negative biopsies, in particular. Conversely, patients predicted to have low baseline levels of PSA were less likely to undergo a biopsy but once biopsied they were more likely to have a biopsy positive for PCa with improvement in the PPV of PSA. We also used 23 SNPs that we and others have validated as risk variants for PCa to define overall genetic risk relative to the general population. We demonstrated using the multiplicative model that the predicted risk agreed well with the observed risk in cohorts of >5,190 patients and >40,000 controls. Combining the PSA correction profile together with the PCa risk profile in a prospective prostate biopsy outcome cohort of 1,307 patients, significantly improved the PPV of PSA in terms of biopsy outcome. The effect of the PCa risk profile was observed in all ranges of PSA levels examined. CONCLUSIONS This study shows that genetic correction of total PSA together with defining genetic risk for PCa, significantly improves the prediction of PCa by measured total PSA. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e400 Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information Julius Gudmundsson Reykjavik, Iceland More articles by this author Jeff Gulcher Reykjavik, Iceland More articles by this author Soren Besenbacher Reykjavik, Iceland More articles by this author Patrick Sulem Reykjavik, Iceland More articles by this author Daniel Gudbjartsson Reykjavik, Iceland More articles by this author Isleifur Olafsson Reykjavik, Iceland More articles by this author Sturla Arinbjarnarson Reykjavik, Iceland More articles by this author Bjarni Agnarsson Reykjavik, Iceland More articles by this author Kristrun Benediktsdottir Reykjavik, Iceland More articles by this author Helgi Isaksson Reykjavik, Iceland More articles by this author Unnur Bjornsdottir Reykjavik, Iceland More articles by this author Gudmundur Eyjolfsson Reykjavik, Iceland More articles by this author Jenny Donovan Bristol, United Kingdom More articles by this author Freddie Hamdy Oxford, United Kingdom More articles by this author William Catalona Chicago, IL More articles by this author Gudmundur Geirsson Reykjavik, Iceland More articles by this author Gudmundur Einarsson Reykjavik, Iceland More articles by this author Rosa Barkardottir Reykjavik, Iceland More articles by this author Eirikur Jonsson Reykjavik, Iceland More articles by this author David Neal Cambridge, United Kingdom More articles by this author Unnur Thorsteinsdottir Reykjavik, Iceland More articles by this author Thorunn Rafnar Reykjavik, Iceland More articles by this author Kari Stefansson Reykjavik, Iceland More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...