. 2022 Apr 21;19(6):331–343. doi: 10.1038/s41585-022-00580-7

Table 1.

Major hereditary cancer syndromes linked with prostate cancer

Gene	Syndrome	Clinical manifestations affecting cancer management (patient and familial implications)^a	Prostate cancer management considerations by selected guidelines for patients with mutations^b
BRCA1 BRCA2	HBOC	Female and male breast cancer Ovarian cancer Prostate cancer Pancreatic cancer Melanoma	NCCN Guidelines Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic Version 1.2022 (ref.⁹) Prostate cancer: PSA screening starting at the age of 40 years with annual intervals Recommend screening for BRCA2 carriers and consider screening for BRCA1 carriers NCCN Prostate Cancer (Version 2.2021)⁷ For mCRPC, DNA genes such as BRCA1, BRCA2, ATM, etc. might inform early platinum therapy or PARP inhibitor therapy NCCN Prostate Cancer Early Detection (Version 2.2020)⁴⁹ Consider shared decision-making for men with BRCA1 or BRCA2 mutations regarding prostate cancer screening starting at the age of 40 years and to consider annual versus biannual screening Philadelphia Prostate Cancer Consensus Conference 2019 (ref.²) Recommend precision medicine clinical trials mCRPC: BRCA2 and BRCA1 inform PARP inhibitor therapy; also inform use of platinum chemotherapy. Consider immunotherapy for DNA MMR gene mutation carriers Consider BRCA2 in active surveillance discussions Prostate cancer screening at the age of 40 years or 10 years before the youngest person in the family was diagnosed with prostate cancer and continue screening with annual intervals (recommended for BRCA2 carriers with consideration for BRCA1 carriers) AUA/ASTRO/SUO Advanced Prostate Cancer 2020 (ref.⁴⁰) Offer PARP inhibitors to patients with deleterious or suspected deleterious germline or somatic homologous recombination repair gene-mutated mCRPC following previous treatment with enzalutamide or abiraterone acetate, and/or a taxane-based chemotherapy. Consider platinum-based chemotherapy as an alternative for patients who cannot use or obtain a PARP inhibitor EAU Prostate Cancer 2020 (ref.⁴¹) Genetic testing for DNA repair mutations for PARP inhibitor therapy in mCRPC
MLH1 MSH2 MSH6 PMS2 EPCAM	Lynch syndrome	Colorectal Endometrial Ovarian Urothelial cancer (renal pelvis, ureteral cancers) Gastric and/or small bowel Pancreatic Prostate Brain	NCCN Prostate Cancer (Version 2.2021)⁷ For mCRPC, consider dMMR or MSI-H status for pembrolizumab Philadelphia Prostate Cancer Consensus Conference 2019 (ref.²) Consider DNA MMR gene mutations for pembrolizumab Consider prostate cancer screening at age 40 years or 10 years before the youngest person in the family was diagnosed with prostate cancer and continue screening with annual intervals AUA/ASTRO/SUO Advanced Prostate Cancer 2020 (ref.⁴⁰) In patients with dMMR or MSI-H mCRPC, offer pembrolizumab
HOXB13	Hereditary prostate cancer	Prostate cancer	Philadelphia Prostate Cancer Consensus Conference 2019 (ref.²) Consider prostate cancer screening at age 40 years or 10 years before the youngest person in the family was diagnosed with prostate cancer and continue screening with annual intervals

Gene

Syndrome

Clinical manifestations affecting cancer management (patient and familial implications)^a

Prostate cancer management considerations by selected guidelines for patients with mutations^b

BRCA1

BRCA2

HBOC

Female and male breast cancer

Ovarian cancer

Prostate cancer

Pancreatic cancer

Melanoma

NCCN Guidelines Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic Version 1.2022 (ref.⁹)

Prostate cancer: PSA screening starting at the age of 40 years with annual intervals Recommend screening for BRCA2 carriers and consider screening for BRCA1 carriers

NCCN Prostate Cancer (Version 2.2021)⁷

For mCRPC, DNA genes such as BRCA1, BRCA2, ATM, etc. might inform early platinum therapy or PARP inhibitor therapy

NCCN Prostate Cancer Early Detection (Version 2.2020)⁴⁹

Consider shared decision-making for men with BRCA1 or BRCA2 mutations regarding prostate cancer screening starting at the age of 40 years and to consider annual versus biannual screening

Philadelphia Prostate Cancer Consensus Conference 2019 (ref.²)

Recommend precision medicine clinical trials

mCRPC: BRCA2 and BRCA1 inform PARP inhibitor therapy; also inform use of platinum chemotherapy. Consider immunotherapy for DNA MMR gene mutation carriers

Consider BRCA2 in active surveillance discussions

Prostate cancer screening at the age of 40 years or 10 years before the youngest person in the family was diagnosed with prostate cancer and continue screening with annual intervals (recommended for BRCA2 carriers with consideration for BRCA1 carriers)

AUA/ASTRO/SUO Advanced Prostate Cancer 2020 (ref.⁴⁰)

Offer PARP inhibitors to patients with deleterious or suspected deleterious germline or somatic homologous recombination repair gene-mutated mCRPC following previous treatment with enzalutamide or abiraterone acetate, and/or a taxane-based chemotherapy. Consider platinum-based chemotherapy as an alternative for patients who cannot use or obtain a PARP inhibitor

EAU Prostate Cancer 2020 (ref.⁴¹)

Genetic testing for DNA repair mutations for PARP inhibitor therapy in mCRPC

MLH1

MSH2

MSH6

PMS2

EPCAM

Lynch syndrome

Colorectal

Endometrial

Ovarian

Urothelial cancer (renal pelvis, ureteral cancers)

Gastric and/or small bowel

Pancreatic

Prostate

Brain

NCCN Prostate Cancer (Version 2.2021)⁷

For mCRPC, consider dMMR or MSI-H status for pembrolizumab

Philadelphia Prostate Cancer Consensus Conference 2019 (ref.²)

Consider DNA MMR gene mutations for pembrolizumab

Consider prostate cancer screening at age 40 years or 10 years before the youngest person in the family was diagnosed with prostate cancer and continue screening with annual intervals

AUA/ASTRO/SUO Advanced Prostate Cancer 2020 (ref.⁴⁰)

In patients with dMMR or MSI-H mCRPC, offer pembrolizumab

HOXB13

Hereditary prostate cancer

Prostate cancer

Philadelphia Prostate Cancer Consensus Conference 2019 (ref.²)

Consider prostate cancer screening at age 40 years or 10 years before the youngest person in the family was diagnosed with prostate cancer and continue screening with annual intervals

ASTRO, American Society for Radiation Oncology; AUA, American Urological Association; dMMR, mismatch repair deficiency; EAU, European Association of Urology; HBOC, hereditary breast and ovarian cancer syndrome; mCRPC, metastatic castration-resistant prostate cancer; MMR, mismatch repair; MSI-H, microsatellite instability high; NCCN, National Comprehensive Cancer Network; PARP, poly(ADP-ribose) polymerase; SUO, Society of Urologic Oncology. ^aClinical trials are important for patients with mutations concerning treatment and management of prostate cancer. Many of the hereditary syndromes in this table have cancerous and non-cancerous disease features beyond prostate cancer that also require management. ^bMultiple NCCN guidelines address management of cancer risks, risk reduction and treatment affecting men and their families.