Hereditary Prostate Cancer: Genes Related, Target Therapy and Prevention

Abstract

Prostate cancer (PCa) is globally the second most diagnosed cancer type and the most common cause of cancer-related deaths in men. Family history of PCa, hereditary breast and ovarian cancer (HBOC) and Lynch syndromes (LS), are among the most important risk factors compared to age, race, ethnicity and environmental factors for PCa development. Hereditary prostate cancer (HPCa) has the highest heritability of any major cancer in men. The proportion of PCa attributable to hereditary factors has been estimated in the range of 5-15%. To date, the genes more consistently associated to HPCa susceptibility include mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) and homologous recombination genes (BRCA1/2, ATM, PALB2, CHEK2). Additional genes are also recommended to be integrated into specific research, including HOXB13, BRP1 and NSB1. Importantly, BRCA1/BRCA2 and ATM mutated patients potentially benefit from Poly (ADP-ribose) polymerase PARP inhibitors, through a mechanism of synthetic lethality, causing selective tumor cell cytotoxicity in cell lines. Moreover, the detection of germline alterations in MMR genes has therapeutic implications, as it may help to predict immunotherapy benefits. Here, we discuss the current knowledge of the genetic basis for inherited predisposition to PCa, the potential target therapy, and the role of active surveillance as a management strategy for patients with low-risk PCa. Finally, the current PCa guideline recommendations are reviewed.

Keywords: genetic testing; genotype–phenotype correlation; hereditary prostate cancer; surveillance.

Figure 1

Frequency of mutations found in HPCa related genes. The proportion of PCa attributable to hereditary factors has been estimated to be 5–15%. The upper part of the iceberg constitutes 7.4–21% and indicates the gene mutation frequencies known so far, while the lower part, constituting 79–92%, represents the portion of genes not yet identified. Partner and localizer of BRCA2 (PALB2); Breast cancer type1 (BRCA1); Checkpoint kinase 2 (CHEK2); Breast cancer type2 (BRCA2); Homeobox B13 (HOXB13); ATM serine/threonine kinase (ATM); Mismatch Repair (MMR); BRCA1 interacting protein C-terminal helicase 1 (BRIP1); Nijmegen Breakage Syndrome 1 (NBS1).

Figure 2

DNA repair pathway in the prostate epithelium involving hereditary prostate cancer (HPCa) related genes: mismatch repair or MMR (A); homologous recombination or HR (B). See text for detailed description. mutS homolog 2 (MSH2); mutS homolog 6 (MSH6); mutL homolog 1 (MLH1); PMS1 homolog 2 (PMS2); Exonuclease 1 (EXO1); δ polymerase (POLD1); DNA ligase I (LIG1); Meiotic recombination 11 (MRE11); Double strand break repair protein (RAD50); Nijmegen disruption syndrome proteins (NBS1); Replication protein A (RPA); ATM serine/threonine kinase (ATM); Breast cancer type1 (BRCA1); Checkpoint kinase 2 (CHEK2); RAD51 recombinase (RAD51); Breast cancer type2 (BRCA2); Partner and localizer of BRCA2 (PALB2).

Figure 3

Management of unaffected family members with positive genetic test.