Genetic Susceptibility to Prostate Cancer

Abstract

Prostate cancer (PCa) is the second most diagnosed cancer type globally and is one of the leading causes of death in men. Genetic susceptibility plays a sig nificant role in PCa development with a reported heritability of 57%. Mutations in the different DNA damage repair (DDR) genes (BRCA1, BRCA2, CHEK2, ATM, and PALB2) and in DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) are hallmark of hereditary prostate cancer (HPCa) and are included in National Comprehensive Cancer Network (NCCN) guidelines for PCa germline genetic testing. In addition to rare high-risk mutations in susceptibility genes, poly genetic inheritance of low-risk germline variants in the form of single-nucleotide polymorphisms (SNPs) may be utilized to distinguish an individual’s susceptibility to PCa onset and progression. Over the past decade, the number of detected variants has increased to 269, due to the genome-wide association studies (GWAS). The large number of identified variants led to the development of polygenic risk scores (PRS) that aggregates common PCa-associated genetic variants into a single mea sure. The incorporation of diverse genetic analyses and PRS is highly anticipated to those individuals with positive PCa family history and may lead to improvements in clinical outcomes for this population through early prevention screening efforts. © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2024.