MP6-16 GERMLINE VARIANTS WITHIN THE PTEN/PI3K AXIS AND ASSOCIATION WITH CASTRATE RESISTANT PROSTATE CANCER AND PROSTATE CANCER SPECIFIC MORTALITY (2015)

You have accessJournal of UrologyProstate Cancer: Markers II1 Apr 2015MP6-16 GERMLINE VARIANTS WITHIN THE PTEN/PI3K AXIS AND ASSOCIATION WITH CASTRATE RESISTANT PROSTATE CANCER AND PROSTATE CANCER SPECIFIC MORTALITY Ryan Kopp, John Sullivan, James Hayes, James Eastham, Kenneth Offit, Joseph Vijai, and Robert Klein Ryan KoppRyan Kopp More articles by this author , John SullivanJohn Sullivan More articles by this author , James HayesJames Hayes More articles by this author , James EasthamJames Eastham More articles by this author , Kenneth OffitKenneth Offit More articles by this author , Joseph VijaiJoseph Vijai More articles by this author , and Robert KleinRobert Klein More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.263AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Early detection of aggressive prostate cancer (PCa) that will lead to castrate resistant prostate cancer (CRPC) and prostate cancer specific mortality (PCSM) is unreliable with current biomarkers. Somatic mutations in the PTEN/PI3K signaling axis are implicated in CRPC development. We determined if germline single nucleotide polymorphisms (SNPs) within this signaling axis are associated with CRPC and PCSM. METHODS We genotyped 1354 individuals of European ancestry diagnosed with localized PCa between June 1988 and December 2007. Blood samples were prospectively collected and de−identified before being genotyped and matched to phenotypic data with follow up current as of November 2013. We identified candidate genes involved with PTEN/PI3K signaling previously implicated in CRPC. Using public ENCODE data we identified potentially functional SNPs at DNAse hypersensitivity and histone methylation sites of PCa cell lines, then created tag SNPs with minor allele frequency >0.05 and r2>0.8. We genotyped 74 SNPs among 12 genes using matrix−assisted laser desorption/ionization time−of−flight (Sequenom iPLEX) then excluded 156 samples and 6 SNPs for genotype calls <80%. The 1198 patients with adequate genotyping included 283 with CRPC and 171 with PCSM. We analyzed associations between 68 SNPs and CRPC and PCSM with Cox proportional hazards models using time interval from diagnosis to event. Multivariate models adjusted for age and PSA at diagnosis, biopsy Gleason sum, stage and treatment. We considered p<0.05 significant for this pilot analysis, but also included Bonferroni correction for multiple testing (p<0.00074). RESULTS The cohort had median age 66 years (IQR 60, 72), biopsy Gleason sum ≤6/7/8−10 in 37%/41%/22%, clinical stage I/II/II in 45%/40%/16%, and median PSA 7.4 (IQR 5.1, 12.7). On multivariable analysis 1 SNP was associated with CRPC (rs11762213 MET, HR 1.64, p=0.035) and 4 SNPs were associated with PCSM (rs38840 MET, HR 1.43, p=0.015; rs8102171 AKT2, HR 0.72, p=0.025; rs137969027 AKT1, HR 0.74, p=0.033; rs3730089 PIK3R1, HR 1.37 p0.047). After correction for multiple testing (p<0.00074), only rs38840 was associated with PCSM on univariate analysis (p=0.00065). CONCLUSIONS This pilot analysis identified SNPs associated with CRPC and PCSM within the PTEN/PI3K axis. These findings require further validation prior to assessment of applicability to PCa screening or current treatment paradigms. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e60 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Ryan Kopp More articles by this author John Sullivan More articles by this author James Hayes More articles by this author James Eastham More articles by this author Kenneth Offit More articles by this author Joseph Vijai More articles by this author Robert Klein More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...