Andrew Siegel MD 1/18/2020
Normal cells become cancer cells when mutations in the DNA (deoxyribonucleic acid) sequence of a gene transform them into a growing and destructive version of their former selves. These abnormal cells can then divide and proliferate aberrantly and without control.
Most mutated DNA occurs by random cellular events or by exposure to environmental toxins. These acquired mutations are referred to as somatic mutations and are not passed on to children. 90% of prostate cancers are based upon these “somatic” mutations. On the other hand, mutated DNA inherited from one’s parents and passed on to children– referred to as a “germline” mutation– is responsible for about 10% of prostate cancers. Inherited germline prostate cancer is often a particularly aggressive cancer, generally more so than a prostate cancer based upon a somatic mutation. Germline mutations are the topic for today’s entry.
Thank you, Peter Linforth from Pixabay for image of DNA above
Germline mutations play a key role in many breast and ovarian cancers. The inherited germline mutations that increase the risk of breast and ovarian cancers in females—BRCA (BReast CAncer) mutations—confer a similar risk for prostate cancer in men. BRCA1 mutations double the risk of metastatic castrate resistant prostate cancer (CRPC) and BRCA2 mutations increase the risk of metastatic CRPC by a factor of 4-6, with earlier onset, higher grade at diagnosis and shorter survival. More than 20% of men with metastatic CRPC are found to have germline mutations, the most common being BRCA2.
Germline mutation assessment versus somatic mutation assessment:
Germline mutation assessment (genetic testing) can help assess for prostate cancer risk as well as influence treatment and prognosis.
Somatic mutation assessment (genomic tumor profiling) examines the genetic material in a prostate cancer specimen and can help predict how aggressively a prostate cancer might behave, how likely it is to advance and metastasize, and inform decision making regarding treatment.
Genetic (germline) testing for prostate cancer is indicated in the following circumstances: early onset prostate cancer, aggressive prostate cancer (Gleason score 7 or greater), metastatic prostate cancer, patients with multiple cancers that include prostate cancer (e.g. prostate cancer and male breast cancer); and prostate cancer patients who have several family members with prostate, breast, ovarian, colorectal or pancreatic cancer.
Multi-gene panel germline testing uses either a blood or saliva sample to determine the presence of a panel of numerous genes commonly implicated in inherited prostate cancer. The most common mutations found are the BRCA2 mutation (accounts for about 50% of hereditary prostate cancer mutations) and Lynch syndrome mutation. Lynch syndrome (hereditary non-polyposis colorectal cancer) is an inherited cancer syndrome causing mutations in DNA repair genes called MMR genes (MisMatch Repair), including MSH2, MSH6, MLH1, PMS2, EPCAM. Because of this predisposition to mutation from the impaired DNA repair, patients with Lynch syndrome have increased risk not only of colorectal cancers, but a host of other cancers including prostate cancer. Additional mutations implicated in inherited prostate cancer are ATM (Ataxia Telangiectasia Mutation), HOXB13 (Homeobox B13) and CHEK2 (Checkpoint Kinase).
Mutation-specific treatments can be informed by the specific germline mutation responsible for the prostate cancer. For example, patients with mutations in DNA repair genes may respond well to poly-ADP ribose polymerase (PARP) inhibitors and platinum-based chemotherapies. Patients with mutations in MMR genes may respond well to immunotherapies (checkpoint inhibitors).
Bottom Line: Germline testing in prostate cancer patients can provide valuable information that informs the prognosis of the disease as well as its treatment, with mutation-specific treatment regimens being increasingly employed. Additionally, if germline mutations are identified, testing of adult family members including siblings and children of the patient can identify those at higher risk and direct appropriate screening. Genetic testing is an exciting and emerging field and is currently incorporated into prostate cancer management on a much more routine basis than it ever has previously.
Wishing you the best of health,
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Dr. Andrew Siegel is a physician and urological surgeon who is board-certified in urology as well as in female pelvic medicine and reconstructive surgery. He is an Assistant Clinical Professor of Surgery at the Rutgers-New Jersey Medical School and is a Castle Connolly Top Doctor New York Metro Area, Inside Jersey Top Doctor and Inside Jersey Top Doctor for Women’s Health. His mission is to “bridge the gap” between the public and the medical community. He is a urologist at New Jersey Urology, the largest urology practice in the United States.
Much of the content of this entry is excerpted from his new book, PROSTATE CANCER 20/20: A Practical Guide to Understanding Management Options for Patients and Their Families
Video trailer for Prostate Cancer 20/20
Preview of Prostate Cancer 20/20
Andrew Siegel MD Amazon author page
Prostate Cancer 20/20 on Apple iBooks
PROSTATE CANCER 20/20: A Practical Guide to Understanding Management Options for Patients and Their Families is now on sale at Audible, iTunes and Amazon as an audiobook read by the author (just over 6 hours).
Dr. Siegel’s other books:
PROMISCUOUS EATING— Understanding and Ending Our Self-Destructive Relationship with Food
MALE PELVIC FITNESS: Optimizing Sexual and Urinary Health
THE KEGEL FIX: Recharging Female Pelvic, Sexual, and Urinary Health
Tags: Andrew Siegel MD, BRCA mutations, genetic testing in prostate cancer, germline mutations, Lynch Syndrome, Prostate Cancer 20/20
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