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Genetics

Prostate cancer is more common in families with a history of any cancer. Men with an affected first-degree relative (father or brother) have more than twice the risk of developing prostate cancer, and those with two first-degree relatives have a five-fold greater risk compared with men with no family history. Increased risk also runs in some ethnic groups, with men of African and African-Caribbean ancestry at particularly high risk – having prostate cancer at higher rates, and having more-aggressive prostate cancers that develop at earlier ages. Large genome-wide association studies have identified over 100 gene variants associated with increased prostate cancer risk. The greatest risk increase is associated with variations in BRCA2 (up to an eight-fold increased risk) and HOXB13 (three-fold increased risk), both of which are involved in repairing DNA damage. Variants in other genes involved in DNA damage repair have also been associated with an increased risk of developing prostate cancer – particularly early-onset prostate cancer – including BRCA1, ATM, NBS1, MSH2, MSH6, PMS2, CHEK2, RAD51D, and PALB2. Additionally, variants in the genome near the oncogene MYC are associated with increased risk. As are single-nucleotide polymorphisms in the vitamin D receptor common in African-Americans, and in the androgen receptor, CYP3A4, and CYP17 involved in testosterone synthesis and signaling. Together, known gene variants are estimated to cause around 25% of prostate cancer cases, including 40% of early-onset prostate cancers.