Hereditary Predisposition to Prostate Cancer: From Genetics to Clinical Implications

Abstract

Prostate cancer (PrCa) ranks among the top five cancers for both incidence and mortality worldwide. A significant proportion of PrCa susceptibility has been attributed to inherited predisposition, with 10-20% of cases expected to occur in a hereditary/familial context. Advances in DNA sequencing technologies have uncovered several moderate- to high-penetrance PrCa susceptibility genes, most of which have previously been related to known hereditary cancer syndromes, namely the hereditary breast and ovarian cancer (BRCA1, BRCA2, ATM, CHEK2, and PALB2) and Lynch syndrome (MLH1, MSH2, MSH6, and PMS2) genes. Additional candidate genes have also been suggested, but further evidence is needed to include them in routine genetic testing. Recommendations based on clinical features, family history, and ethnicity have been established for more cost-efficient genetic testing of patients and families who may be at an increased risk of developing PrCa. The identification of alterations in PrCa predisposing genes may help to inform screening strategies, as well as treatment options, in the metastatic setting. This review provides an overview of the genetic basis underlying hereditary predisposition to PrCa, the current genetic screening recommendations, and the implications for clinical management of the disease.

Keywords: genetic testing; germline variants; hereditary cancer syndrome; prostate cancer.

Figure 1

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 (https://www.ncbi.nlm.nih.gov/clinvar/, accessed in 20 May 2020) are also represented on each gene. The location of the variants is shown by lollipop structures. The x-axis represents the number of amino acid residues and displays the protein domains encoded by each gene.

Figure 2

PrCa risk loci identified by genome-wide association studies (GWAS). The circles represent the location of loci significantly associated with PrCa risk (p-value ≤ 5.0 × 10⁻⁸) along the genome, divided into separate chromosomes. Data retrieved from the NHGRI-EBI Catalogue of published GWAS (http://www.ebi.ac.uk/gwas) and plotted using the PhenoGram software.