Genetic predisposition to prostate cancer: an update

Abstract

Improvements in DNA sequencing technology and discoveries made by large scale genome-wide association studies have led to enormous insight into the role of genetic variation in prostate cancer risk. High-risk prostate cancer risk predisposition genes exist in addition to common germline variants conferring low-moderate risk, which together account for over a third of familial prostate cancer risk. Identifying men with additional risk factors such as genetic variants or a positive family history is of clinical importance, as men with such risk factors have a higher incidence of prostate cancer with some evidence to suggest diagnosis at a younger age and poorer outcomes. The medical community remains in disagreement on the benefits of a population prostate cancer screening programme reliant on PSA testing. A reduction in mortality has been demonstrated in many studies, but at the cost of significant amounts of overdiagnosis and overtreatment. Developing targeted screening strategies for high-risk men is currently the subject of investigation in a number of prospective studies. At present, approximately 38% of the familial risk of PrCa can be explained based on published SNPs, with men in the top 1% of the risk profile having a 5.71-fold increase in risk of developing cancer compared with controls. With approximately 170 prostate cancer susceptibility loci now identified in European populations, there is scope to explore the clinical utility of genetic testing and genetic-risk scores in prostate cancer screening and risk stratification, with such data in non-European populations eagerly awaited. This review will focus on both the rare and common germline genetic variation involved in hereditary and familial prostate cancer, and discuss ongoing research in exploring the role of targeted screening in this high-risk group of men.

Keywords: Familial prostate cancer; Germline genetics; Hereditary prostate cancer; Prostate cancer; Prostate cancer risk.

Fig. 1

Reproduced and adapted from Maniolo et al. Diagram showing the spectrum of genetic variants in polygenic disease i.e. PrCa. The X-axis plots the risk allele frequency and effect size along the y-axis. The top right corner represents common variants with large effect sizes (none known). The bottom left corner represents rare variants with small effect size. Such variants would be of limited clinical interest. Candidate gene and linkage analyses have discovered rare variants (i.e. BRCA1/2, HOXB13 which produce moderate effect sizes. Genome wide association studies (GWAS) have discovered common variants conferring small to modest effect sizes. Those variants circled in yellow represent the germline genetic variations we incorporate into PRS; (common variants) and panel testing (eg. BRCA2) [4]. (Reprinted by permission from Springer Nature: Nature. Finding the missing heritability of complex diseases, Maniolo et al. ©2009)

Fig. 2

Reproduced and modified from Klein et al. Schematic representation of the proportion of PrCa caused by HPC and familial PrCa [9]. Reprinted with permission from Springer Nature: Prostate Cancer and Prostatic Diseases. Does a family history of prostate cancer result in more aggressive disease? Klein et al. ©1999

Fig. 3

Reproduced from Leongamornlert et al. Distribution of pathogenic germline variants in 191 men with at least  ≥ 3 cases of PrCa in their family [27]. Reprinted by permission from Springer Nature: on behalf of Cancer Research UK: Springe Nature. Br J C. Frequent germline deleterious variants in DNA repair genes in familial prostate cancer cases are associated with advanced disease, Leongamornlert et al. ©(2014)

Fig. 4

Reproduced from Carter et al. Risk of disease upgrading after diagnostic biopsy among carriers and noncarriers of variants in BRCA2 only who were initially diagnosed with GGG 1 (Gleason score 3 + 3) : a upgrading after diagnostic biopsy to GGG 2 or above (Gleason score 3 + 4 or above); b upgrading after diagnostic biopsy to GGG 3 or above (Gleason score 4 + 3 or above) [53]. Reprinted from European Urology, 75(5): Carter et al. Germline variants in ATM and BRCA1/2 are Associated with Grade Reclassification in Men on Active Surveillance for Prostate Cancer, p743-49 ©2019, with permission from Elsevier

Fig. 5

Reproduced from Lecarpentier et al. Predicted PrCa cumulative risk for male carriers of BRCA2 variants by percentiles of PrCa polygenic risk score that was constructed by using results from population-based studies [60]. Reprinted with permission © 2017 American Society of Clinical Oncology. All rights reserved