Prostate Cancer Genetics

Prostate cancer is a complex disease influenced by both genetic and environmental factors. In most cases, the prostate cells accumulate genetic alterations during aging, which subsequently lead to uncontrolled cell growth and the formation of tumors. In rare cases, genetic predisposition can increase the risk of developing prostate cancer among:

• Carriers of BRCA1/2, ATM, HOXB13, CHEK2, NBN or PALB2 gene mutations
• Individuals with Lynch Syndrome
• Individuals with a strong family history of prostate cancer

This article discusses the genetic factors of prostate cancer and highlights the importance of genetic counseling and screening for individuals with a family history or predisposition to the disease.

Researchers have identified several genetic alterations associated with an increased risk of prostate cancer. While many of these abnormalities run in the family, it is also possible to acquire them sporadically. Genes associated with prostate cancer are BRCA1 and BRCA2.

Mutations in these genes are well-known for their association with breast and ovarian cancers. They have also been linked to an increased risk of prostate cancer, particularly in families with a history of multiple cancers. The relative risk of developing prostate cancer in male carriers with these mutations are

• BRCA1: About three times more than noncarriers
• BRCA2: As high as eight times more than noncarriers

The ongoing IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation carriers and controls) clinical trial has also found that BRCA2 carriers

• Have a younger onset of the disease
• Tend to have more advanced and aggressive disease at the time of diagnosis
• Tend to have a poorer prognosis

Mutations in BRCA genes are seen in 1 in 40 people of Ashkenazi Jewish ancestry, compared to 1 in 400 people in the general population.

Other gene mutations have also been identified in some families with a history of hereditary prostate cancer. These mutations are relatively rare but are associated with an increased risk of prostate cancer:

• Ataxia telangiectasia mutated (ATM)
• Homeobox B13 (HOXB13) – A rare inherited mutation in HOXB13 specific to African ancestry has been discovered. It is linked to a 2.4-fold increase in risk of prostate cancer, particularly the more aggressive and advanced forms.
• Checkpoint kinase 2 (CHEK2)
• Nibrine (NBN; also called NBS1)
• Partner and localizer of BRCA2 (PALB2)
• Lynch syndrome-causing gene mutations – (MLH1, MSH2, MSH6 and PMS2)

For individuals who have a genetic predisposition to cancer, they can take proactive measures to manage their risk, and potentially prevent or detect prostate cancer at an early, more treatable stage.

For individuals with a family history of prostate cancer, it is important to consult a genetic counselor and explore:

• Active cancer surveillance, including the limitations and uncertainties of various prostate cancer screening tests
• Basic cancer genetics
• Genetic testing options (including genetic germline or familial testing) and how to interpret the test results

The US National Comprehensive Cancer Network (NCCN) recommends genetic counseling and genetic screening (and shared decision-making) for men with:

• Brother(s), father or other family members (including deceased ones) diagnosed with prostate cancer at age 60 and below
• Having three or more cancers diagnosed at age 50 and below on the same side of the family. Examples of cancer include breast, endometrial, ovarian, colorectal, bile duct, pancreatic, gastric, kidney, prostate and urothelial cancer.
• Ashkenazi Jewish ancestry
• Other types of cancer

The NCCN recommendations for BRCA2 mutation carriers include “prostate cancer screening … at age 40 years… and to consider screening at annual intervals rather than every other year”.

The American Cancer Society recommends that “if you are African American or have a father or brother who had prostate cancer before age 65, you should have this talk (on the informed decision) with a healthcare provider starting at age 45”.

Learn more: Prostate Cancer Genetic Testing