Rare germline genetic variants and risk of aggressive prostate cancer

Abstract

Few genetic risk factors have been demonstrated to be specifically associated with aggressive prostate cancer (PrCa). Here, we report a case‐case study of PrCa comparing the prevalence of germline pathogenic/likely pathogenic (P/LP) genetic variants in 787 men with aggressive disease and 769 with nonaggressive disease. Overall, we observed P/LP variants in 11.4% of men with aggressive PrCa and 9.8% of men with nonaggressive PrCa (two‐tailed Fisher's exact tests, P = .28). The proportion of BRCA2 and ATM P/LP variant carriers in men with aggressive PrCa exceeded that observed in men with nonaggressive PrCa; 18/787 carriers (2.3%) and 4/769 carriers (0.5%), P = .004, and 14/787 carriers (0.02%) and 5/769 carriers (0.01%), P = .06, respectively. Our findings contribute to the extensive international effort to interpret the genetic variation identified in genes included on gene‐panel tests, for which there is currently an insufficient evidence‐base for clinical translation in the context of PrCa risk.

Mutations in ATM, NBN and BRCA2 predispose to aggressive prostate cancer in Poland

“…ATM has been implicated in increased risk of metastatic and lethal prostate cancer. [19][20][21][22][23] In most recent study, ATM mutations were detected in 0.7% of men with early onset PCa vs 0.2% in controls (OR = 4.1, P = .1). 18 In aggregate, studies to date suggest that ATM variants predispose to aggressive and early onset PCa, but each includes small number of carriers, and further research is needed.…”

“…Importantly, 50% of cancers diagnosed among ATM carriers were of Gleason score 8 to 10, compared to 22.7% in noncarriers ( P = .03). ATM has been implicated in increased risk of metastatic and lethal prostate cancer 19‐23 . In most recent study, ATM mutations were detected in 0.7% of men with early onset PCa vs 0.2% in controls (OR = 4.1, P = .1) 18 .…”

A Polygenic Risk Score Predicts Incident Prostate Cancer Risk in Older Men but Does Not Select for Clinically Significant Disease

“…Genome-wide association and twin studies have estimated the heritability of prostate cancer to be 57% [ 20 , 21 ]. Whilst a small proportion of this heritability is explained by rare pathogenic variants in monogenic disease-associated genes [ 22 , 23 , 24 , 25 ], a larger proportion is attributable to common variants identified by genome-wide association studies (GWAS). A PRS aggregates the effect of these common variants into a single measure of genetic risk that can then be used alongside conventional prostate cancer risk factors in a risk prediction model.…”

Hereditary Predisposition to Prostate Cancer: From Genetics to Clinical Implications

“… Pathogenic germline variants reported in the established, and potentially clinically actionable, PrCa predisposing genes recommended for genetic testing for PrCa [ 30 , 53 , 55 , 58 , 82 , 87 , 88 , 89 , 90 , 96 , 115 , 116 , 117 , 118 , 119 , 120 ] ( Table S1 ). Missense variants classified as “pathogenic/likely pathogenic” by ClinVar ( , accessed in 20 May 2020) are also represented on each gene.…”

“…The advances in NGS technologies have greatly facilitated the use of multigene panel testing for hereditary cancer risk evaluation and management in clinical practice. For PrCa, multigene panel testing has driven the identification of several alterations in genes of moderate-penetrance (usually with an RR of 2- to 5-fold) contributing to the complex and heterogeneous genetic architecture of PrCa [ 87 , 89 , 90 , 96 , 118 ]. As previously described, inherited alterations in DNA-damage repair genes have been consistently implicated in PrCa, being described in a range of 5% to 12% of the localized and metastatic stages of the disease, respectively [ 90 ].…”