Hereditary prostate cancer

Prostate cancer is a malignancy of the prostate gland with variable clinical behaviour, primarily affecting older men. The disease ranges from indolent, organ-confined tumours – often detected through PSA testing – to aggressive forms characterised by extracapsular extension, regional or distant metastases, and high Gleason scores at diagnosis. Both familial clustering and hereditary forms are recognised. Familial prostate cancer is observed in pedigrees with multiple affected first-degree relatives, whereas hereditary prostate cancer follows more defined patterns of inheritance. Syndromic forms include syndrome and , in which prostate cancer represents part of a broader tumour spectrum. Tumours arising in men with germline pathogenic BRCA2 variants are more frequently associated with aggressive disease features, including higher Gleason scores, advanced tumour stage at diagnosis, and elevated serum PSA levels. Disease onset occures in adulthood, most commonly from middle age onwards, with familial cases often demonstrating clustering across successive generations.

Prostate cancer is the most commonly diagnosed cancer in men in Europe and one of the most frequently diagnosed malignancies in men worldwide. Germline mutations are detected in an estimated 12–17% of men with metastatic prostate cancer (vs. ~5% in localized disease).

A large number of genes have been associated with prostate cancer susceptibility. Many of these genes are involved in DNA damage response pathways, including homologous recombination repair (e.g., BRCA1, BRCA2, PALB2) and mismatch repair (e.g., MLH1, MSH2, MSH6, PMS2). However, not all prostate cancer susceptibility genes are related to DNA repair, as exemplified by HOXB13. Among the known genetic risk factors, germline pathogenic variants in BRCA2 represent the most well-established high-risk association and are linked to aggressive disease features. Additional examples include BRCA1, which confers a more moderate increase in prostate cancer risk, and HOXB13, particularly the founder p.G84E variant, which is associated with familial prostate cancer.

Most hereditary cancer syndromes associated with prostate cancer, including those involving BRCA1, BRCA2, HOXB13 and mismatch repair genes, follow an autosomal dominant pattern of inheritance with variable penetrance. However, the genetic architecture of prostate cancer is heterogeneous and also includes polygenic risk factors. Classical autosomal recessive inheritance plays only a minor role and is rarely implicated in prostate cancer predisposition.

• Where prostate cancer is suspected to have a genetic cause, molecular genetic testing can identify the underlying condition and confirm a clinical suspicion.
• The identified entity guides further clinical management and is a prerequisite for targeted medical care; therapeutic options are evaluated individually by the treating physicians.
• Identification of the underlying pathogenic germline variant enables predictive testing of at-risk family members and provides information relevant to family planning.

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