PURPOSE: To identify single nucleotide polymorphisms (SNPs) associated with development of erectile dysfunction (ED) among prostate cancer patients treated withradiation therapy. METHODS AND MATERIALS: A 2-stage genome-wide association study was performed. Patients were split randomly into a stage I discovery cohort (132 cases, 103 controls) and a stage II replication cohort (128 cases, 102 controls). The discovery cohort was genotyped using Affymetrix 6.0 genome-wide arrays. The 940 top ranking SNPs selected from the discovery cohort were genotyped in the replication cohort using Illumina iSelect custom SNP arrays. RESULTS: Twelve SNPs identified in the discovery cohort and validated in the replication cohort were associated with development of ED following radiation therapy (Fisher combined P values 2.1×10(-5) to 6.2×10(-4)). Notably, these 12 SNPs lie in or near genes involved in erectile function or other normal cellular functions (adhesion and signaling) rather than DNA damage repair. In a multivariable model including nongenetic risk factors, the odds ratios for these SNPs ranged from 1.6 to 5.6 in the pooled cohort. There was a striking relationship between the cumulative number of SNP risk alleles an individual possessed and ED status (Sommers' D P value=1.7×10(-29)). A 1-allele increase in cumulative SNP score increased the odds for developing ED by a factor of 2.2 (P value=2.1×10(-19)). The cumulative SNP score model had a sensitivity of 84% and specificity of 75% for prediction of developing ED at the radiation therapy planning stage. CONCLUSIONS: This genome-wide association study identified a set of SNPs that are associated with development of ED following radiation therapy. These candidate genetic predictors warrant more definitive validation in an independent cohort.
RCT Entities:
PURPOSE: To identify single nucleotide polymorphisms (SNPs) associated with development of erectile dysfunction (ED) among prostate cancerpatients treated with radiation therapy. METHODS AND MATERIALS: A 2-stage genome-wide association study was performed. Patients were split randomly into a stage I discovery cohort (132 cases, 103 controls) and a stage II replication cohort (128 cases, 102 controls). The discovery cohort was genotyped using Affymetrix 6.0 genome-wide arrays. The 940 top ranking SNPs selected from the discovery cohort were genotyped in the replication cohort using Illumina iSelect custom SNP arrays. RESULTS: Twelve SNPs identified in the discovery cohort and validated in the replication cohort were associated with development of ED following radiation therapy (Fisher combined P values 2.1×10(-5) to 6.2×10(-4)). Notably, these 12 SNPs lie in or near genes involved in erectile function or other normal cellular functions (adhesion and signaling) rather than DNA damage repair. In a multivariable model including nongenetic risk factors, the odds ratios for these SNPs ranged from 1.6 to 5.6 in the pooled cohort. There was a striking relationship between the cumulative number of SNP risk alleles an individual possessed and ED status (Sommers' D P value=1.7×10(-29)). A 1-allele increase in cumulative SNP score increased the odds for developing ED by a factor of 2.2 (P value=2.1×10(-19)). The cumulative SNP score model had a sensitivity of 84% and specificity of 75% for prediction of developing ED at the radiation therapy planning stage. CONCLUSIONS: This genome-wide association study identified a set of SNPs that are associated with development of ED following radiation therapy. These candidate genetic predictors warrant more definitive validation in an independent cohort.
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Authors: Christian Nicolaj Andreassen; Barry S Rosenstein; Sarah L Kerns; Harry Ostrer; Dirk De Ruysscher; Jamie A Cesaretti; Gillian C Barnett; Alison M Dunning; Leila Dorling; Catharine M L West; Neil G Burnet; Rebecca Elliott; Charlotte Coles; Emma Hall; Laura Fachal; Ana Vega; Antonio Gómez-Caamaño; Christopher J Talbot; R Paul Symonds; Kim De Ruyck; Hubert Thierens; Piet Ost; Jenny Chang-Claude; Petra Seibold; Odilia Popanda; Marie Overgaard; David Dearnaley; Matthew R Sydes; David Azria; Christine Anne Koch; Matthew Parliament; Michael Blackshaw; Michael Sia; Maria J Fuentes-Raspall; Teresa Ramon Y Cajal; Agustin Barnadas; Danny Vesprini; Sara Gutiérrez-Enríquez; Meritxell Mollà; Orland Díez; John R Yarnold; Jens Overgaard; Søren M Bentzen; Jan Alsner Journal: Radiother Oncol Date: 2016-07-18 Impact factor: 6.280