title: Population-standardized genetic risk score: the SNP-based method of choice for inherited risk assessment of prostate cancer.
abstract: Several different approaches are available to clinicians for determining prostate cancer (PCa) risk. The clinical validity of various PCa risk assessment methods utilizing single nucleotide polymorphisms (SNPs) has been established; however, these SNP-based methods have not been compared. The objective of this study was to compare the three most commonly used SNP-based methods for PCa risk assessment. Participants were men (n = 1654) enrolled in a prospective study of PCa development. Genotypes of 59 PCa risk-associated SNPs were available in this cohort. Three methods of calculating SNP-based genetic risk scores (GRSs) were used for the evaluation of individual disease risk such as risk allele count (GRS-RAC), weighted risk allele count (GRS-wRAC), and population-standardized genetic risk score (GRS-PS). Mean GRSs were calculated, and performances were compared using area under the receiver operating characteristic curve (AUC) and positive predictive value (PPV). All SNP-based methods were found to be independently associated with PCa (all P < 0.05; hence their clinical validity). The mean GRSs in men with or without PCa using GRS-RAC were 55.15 and 53.46, respectively, using GRS-wRAC were 7.42 and 6.97, respectively, and using GRS-PS were 1.12 and 0.84, respectively (all P < 0.05 for differences between patients with or without PCa). All three SNP-based methods performed similarly in discriminating PCa from non-PCa based on AUC and in predicting PCa risk based on PPV (all P > 0.05 for comparisons between the three methods), and all three SNP-based methods had a significantly higher AUC than family history (all P < 0.05). Results from this study suggest that while the three most commonly used SNP-based methods performed similarly in discriminating PCa from non-PCa at the population level, GRS-PS is the method of choice for risk assessment at the individual level because its value (where 1.0 represents average population risk) can be easily interpreted regardless of the number of risk-associated SNPs used in the calculation.
authors.affiliation: NorthShore University HealthSystem, Program for Personalized Cancer Care, 1001 University Place, Evanston, IL 60201, USA.
authors.forename: Carly A
authors.initials: CA
authors.lastname: Conran
authors.affiliation: NorthShore University HealthSystem, Program for Personalized Cancer Care, 1001 University Place, Evanston, IL 60201, USA; Fudan Institute of Urology, Huashan Hospital, Fudan University, 12 Mid-Wulumuqi Road, Shanghai 200040, P.R. China, .
authors.forename: Rong
authors.initials: R
authors.lastname: Na
authors.affiliation: Center for Genomic Translational Medicine and Prevention, School of Public Health, Fudan University, 138 Yixueyuan Road, Shanghai 200032, P.R. China.
authors.forename: Haitao
authors.initials: H
authors.lastname: Chen
authors.affiliation: NorthShore University HealthSystem, Program for Personalized Cancer Care, 1001 University Place, Evanston, IL 60201, USA.
authors.forename: Deke
authors.initials: D
authors.lastname: Jiang
authors.affiliation: Fudan Institute of Urology, Huashan Hospital, Fudan University, 12 Mid-Wulumuqi Road, Shanghai 200040, P.R. China.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Lin
authors.affiliation: NorthShore University HealthSystem, Program for Personalized Cancer Care, 1001 University Place, Evanston, IL 60201, USA.
authors.forename: S Lilly
authors.initials: SL
authors.lastname: Zheng
authors.affiliation: NorthShore University HealthSystem, Program for Personalized Cancer Care, 1001 University Place, Evanston, IL 60201, USA.
authors.forename: Charles B
authors.initials: CB
authors.lastname: Brendler
authors.affiliation: NorthShore University HealthSystem, Program for Personalized Cancer Care, 1001 University Place, Evanston, IL 60201, USA; Fudan Institute of Urology, Huashan Hospital, Fudan University, 12 Mid-Wulumuqi Road, Shanghai 200040, P.R. China; Center for Genomic Translational Medicine and Prevention, School of Public Health, Fudan University, 138 Yixueyuan Road, Shanghai 200032, P.R. China, .
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Xu
mesh_terms: D058891:5-alpha Reductase Inhibitors / Q000627:therapeutic use; D000368:Aged; D000483:Alleles; D000068538:Dutasteride / Q000627:therapeutic use; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics*; D018570:Risk Assessment; D016896:Treatment Outcome
chemical_list: D058891:5-alpha Reductase Inhibitors; D000068538:Dutasteride