by Dr. C.H. Weaver M.D. updated 3/2023
Prostate cancer, can be caused by changes (mutations) in specific genes which are inherited; these are called germline mutations. Germline prostate cancer causing mutations are found in 12-17% of men with metastatic prostate cancer and 7% of men with early-stage disease. An individuals genetic information may inform how healthcare providers screen, diagnose, and treat prostate cancer, as well as enable them to enroll in a clinical trial. These compelling findings provide a strong reason for expanding the use of genetic testing in men diagnosed with prostate cancer consistent with existing professional medical guidelines.1,2,5,10
About Prostate Cancer
One in nine American men will have prostate cancer during his lifetime. Prostate cancer is the second leading cause of cancer death among American men and is the most commonly diagnosed malignancy. Currently, there are nearly 2.9 million American men living with the disease and every 18 minutes another American man dies from prostate cancer.
Hereditary cancer testing can help inform treatment decisions for men with prostate cancer, including whether to pursue active surveillance, increased screening for secondary cancers and potentially for treatment selection with PARP inhibitors or other precision medicines in the future. Additionally, once men know they carry an inherited mutation, they can encourage their family members to get tested to learn if they’re at increased risk for cancer and potentially help them prevent future cancers.
The Basics of BRCA Mutations
Both men and women have the BRCA1 and BRCA2 genes in their cells. The BRCA1 and BRCA1 genes are responsible for helping cells repair DNA damage. If BRCA genes are mutated, the DNA damage cannot be correctly repaired. Tests have been developed to help determine if BRCA genes are mutated or not. The BRCA gene mutations happen in two different ways:
Somatic Mutations of the BRCA Gene are “acquired” DNA alterations, they occur after conception and are not passed on to children. Somatic, or acquired, BRCA mutations are only found in the cancer cells. They are the most common cause of cancer and occur from damage to genes in an individual cell during a person’s life. These mutations are not hereditary. Genomic testing looks for these abnormalities in a patient’s cancer cells and can help determine the best course of treatment for it.
Germline Mutations of the BRCA Gene are DNA alterations that are inherited from a parent – in the germ cells (sperm and egg). When a gene mutation is inherited, that means the mutation is present in every cell in the body. Germline mutations account for ~ 10% of all cancers. Testing for germline mutations is usually performed on blood or saliva and will identify inherited mutations in genes and can be performed in individuals with and without cancer.
What Does This Mean for Prostate Cancer?
Men who have a BRCA mutation are at a higher risk for developing prostate cancer than men without a BRCA mutation and are more likely to be diagnosed with an aggressive form of prostate cancer. The National Comprehensive Cancer Network (NCCN) Prostate Cancer guidelines now recommend testing for germline DNA repair gene mutations in patients with high-risk and metastatic Prostate Cancer, regardless of family history.
A consensus panel has recommended the following.
- All men with metastatic prostate cancer should undergo comprehensive gene panel testing to help determine precision therapy or clinical trial eligibility.
- Men who have a family history that suggests hereditary prostate cancer such as men diagnosed with prostate cancer at a young age, who died from prostate cancer, or who had metastatic disease, or family history suggestive of other hereditary cancer syndromes such as hereditary breast and ovarian cancer or Lynch syndrome.
- The following genes were endorsed for testing:
- BRCA2, BRCA1, and DNA mismatch repair genes in men with metastatic prostate cancer.
- BRCA2 among men with non-metastatic disease, particularly to inform active surveillance.
- BRCA2 and HOXB13 among men who do not have a diagnosis of prostate cancer but fit the family history criteria for prostate cancer screening.
- Screening should begin at age 40 or 10 years prior to the age of the youngest prostate cancer diagnosis in the family among BRCA2 carriers.
Germline Testing for Prostate Cancer Active Surveillance
Physicians have begun to propose that germline testing be performed for all patients at the time of prostate cancer diagnosis, even those with low-risk disease.
Overall 60% of men who report no risk factors like family history of prostate cancer will have a genetic mutation. Many physicians now believe universal testing should be recommended for all men diagnosed with cancer of any grade or stage. Genetic testing is inexpensive and can identify germline mutations associated with prostate cancer risk and aggressiveness including BRCA2, ATM and MSH2 mutations.
Individuals at high genetic risk for prostate cancer should be followed more carefully based on the interim results from the IMPACT trial (Identification of Men with a genetic predisposition to ProstAte Cancer) which demonstrated that targeted screening in men at higher genetic risk with mutated BRCA2 genes can identify more men with higher-grade disease.
Individuals at higher genetic risk with a BRCA2 mutation have are more likely to have higher grade tumors and metastatic more lethal cancers. They should discuss whether they might benefit from more active surveillance (more frequent biopsies) with their managing physician.
Known Germline Mutations
- Mutations in BRCA1 or BRCA2 genes;
- Lynch Syndrome (the most common cause of hereditary colon cancer, this genetic condition can cause other cancers, including prostate cancer);
- Li-Fraumeni syndrome (a mutated p53 gene, linked to aggressive prostate cancer); and
- Mutations in other genes, including ATM, PALB2, CHEK2, RAD51D, ATR, NBN, GEN1, RAD51C, MRE11A, BRIP1, and FAM175A.
What Can Men at Increased Risk Do?
Lifestyle Changes – a recent study showed that among men at high genetic risk for prostate cancer, those with a healthy lifestyle lowered their risk of dying of prostate cancer by 46 percent, compared to men with the least healthy lifestyle. The healthy lifestyle score was based on six factors: not smoking; having a body mass index (BMI) lower than 30; exercising; having a high intake of tomatoes and fatty fish; and having a low intake of processed meat.5
References:
- Giri et al., “Implementation of Germline Testing for Prostate Cancer: Philadelphia Prostate Cancer Consensus Conference 2019,” Journal of Clinical Oncology.
- Robert Reid, M.D., Inherited Germline Mutations in Men with Prostate Cancer. Poster Board E4; 2018 Genitourinary Cancer Symposium; Abstract 357.
- Page EC, Bancroft EK, Brook MN, et al. Interim results from the IMPACT study: Evidence for prostate-specific antigen screening in BRCA2 mutation carriers [published online September 16, 2019]. Eur Urol. doi:10.1016/j.eururo.2019.08.019
- https://www.pcf.org/blog/benefits-of-a-healthy-lifestyle-in-men-at-high-risk-of-prostate-cancer/
-
Pritchard C, Mateo J, Walsh M, et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. The New England Journal of Medicine. Abstract. July 6, 2016DOI: 10.1056/NEJMoa1603144
-
Ewing CM, Ray AM, Lange EM et al. Germline mutations in HOXB13 and prostate-cancer risk. New England Journal of Medicine. 2012;366:141-9.
-
Amundadottir LT, Sulem P, Gudmundsson J et al. A Common Variant Associated with Prostate Cancer in European and African Populations. Nature Genetics. Early Online Publication May 7, 2006.
-
Ewing CM, Ray AM, Lange EM et al. Germline mutations in HOXB13 and prostate-cancer risk. New England Journal of Medicine. 2012;366:141-9.
-
Jonsson P, Bandlamudi C, Cheng ML, et al. Tumour lineage shapes BRCA-mediated phenotypes. Nature 2019;571:576-9.
-
Robinson D, Van Allen EM, Wu YM, et al. Integrative Clinical Genomics of Advanced Prostate Cancer. Cell 2015;162:454.
