Clinical Utility of Germline Genetic Testing in Japanese Men Undergoing Prostate Biopsy

Abstract

Background Multiple common variants and also rare variants in monogenic risk genes such as BRCA2 and HOXB13 have been reported to be associated with risk of prostate cancer (PCa); however, the clinical setting in which germline genetic testing could be utilized for PCa diagnosis remains obscure. Herein, we tested the clinical utility of a 16 common-variant based polygenic risk score (PRS) that have been developed previously for Japanese, and also evaluated the frequency of PCa associated rare variants in a prospective cohort of Japanese men undergoing prostate biopsy. Methods 1,336 patients undergoing first prostate biopsy were included. PRS was calculated based on the genotype of 16 common variants and sequencing of eight prostate cancer-associated genes was performed by multiplex PCR-based target sequencing. PRS was combined with clinical factors in logistic regression models to assess whether addition of PRS improves the prediction of biopsy positivity. Results The top PRS decile was associated with an odds ratio of 4.10 (95% confidence interval = 2.46 to 6.86) with reference to the patients at average risk, and the estimated lifetime absolute risk approached 20%. Among the patients with PSA 2–10 ng/ml who had pre-biopsy MRI, high PRS had an equivalent impact on biopsy positivity as a positive MRI finding. Rare variants were detected in 19 (2.37%) and 7 (1.31%) patients with positive and negative biopsies, with BRCA2 variants being the most prevalent. There was no association between PRS and high-risk rare variants. Conclusions Germline genetic testing could be clinically useful in both pre- and post-PSA screening settings.

A west African ancestry‐associated SNP on 8q24 predicts a positive biopsy in African American men with suspected prostate cancer following PSA screening

“…25,27,28 More recently, SNPs have been incorporated into prediction algorithms in post-PSA setting. 16,17,[29][30][31][32][33] The Stockholm3 (STHLM3) test, which combines clinical variables, five plasma protein markers, and a GRS derived from 101 PCa susceptibility SNPs, has been shown to reduce the number of performed prostate biopsies while maintaining sensitivity for clinically significant diseases in European descendants. 17,[29][30][31][32][33] However, there has been no prior report using SNPs to enhance the prediction of PCa risk for biopsy referral in AA men with elevated PSA.…”

“…While considerable efforts have been directed towards the first application, [11][12][13][14][15] limited research has focused on assessing the utility of these SNPs in the post-PSA setting. [16][17][18][19] Notably, research regarding this second application has been particularly scarce in AA men.…”

Polygenic risk score in prostate cancer

“…When first applied for clinical use in the early 2000s [15], the PRS was conceptualized as a single value, combinatory estimate for an individual's genetic risk for disease using an additive sum of effect size estimated from GWAS summary statistics. Previous studies have described the potential clinical use of PRS for cancer and other common diseases, which range from risk prediction, informing decision-making during screening, guiding prevention strategies, and assisting personal understanding of individual lifetime risk [11,16,17 ▪▪ ,18 ▪▪ ].…”

The Combined Effect of Polygenic Risk Score and Prostate Health Index in Chinese Men Undergoing Prostate Biopsy

“…Our previous study also suggested that PRS could significantly predict the lifetime risk of PCa in the Chinese population [ 7 ]. It may also significantly and independently predict prostate biopsy outcomes [ 8 , 9 ].…”

“…The incorporation between PRS and PSA for predicting PCa was reported in different studies with different populations including European [ 13 , 14 ], Finnish [ 15 , 16 ], Japanese [ 8 ], and Chinese [ 17 ]. Studies also investigated the combined effect of PRS and the novel approaches and suggested that PRS could provide significant predictive value for PCa in addition to PCA3, 4K Score, or mpMRI [ 6 , 16 , 17 ].…”