Normal cells become cancer cells (malignant cells) when mutations in the DNA (deoxyribonucleic acid) sequence of a gene transform cells into a growing and destructive version of their former selves. These abnormal cells can then divide and multiply without control. Although DNA mutations can be inherited, it is much more common for DNA mutations to occur by one’s exposure to environmental toxins or from random cellular events. Under normal circumstances, the body repairs damaged DNA, but with cancer cells the damaged DNA is unable to be repaired.
The last few years have witnessed a dramatic increase in our understanding of inherited mutations (“germline” mutations) as important predisposing causes of aggressive prostate cancer. About 10% of prostate cancers are on the basis of inherited germline mutations. “Germline” mutations are DNA mutations that are inherited from one’s mother, father, or both parents. These inherited mutations have been present in every cell in the body since birth. This is as opposed to “somatic” mutations that are mutations that have occurred after birth and are not passed on to children. 90% of prostate cancer is thought to be due to non-inherited, acquired somatic mutations.
Germline mutations play a key role in many breast and ovarian cancers and some inherited germline mutations that increase the risk of these cancers in females—BRCA (BReast CAncer) mutations—do the same in terms of risk for prostate cancer in men. BRCA1 mutations double the risk of metastatic castrate resistant prostate cancer (prostate cancer that has spread and is resistant to treatments that decrease testosterone levels or activity) and BRCA2 mutations increase the risk of metastatic castrate resistant prostate cancer by a factor of 4-6, with earlier onset, higher grade at diagnosis and shorter survival. More than 20% of men with metastatic castrate resistant prostate cancers are found to have germline mutations, most commonly BRAC2.
Germline mutation assessment (genetic testing) helps assess one’s risk for prostate cancer. Somatic mutation assessment (genomic testing) examines the genes in a prostate cancer specimen and helps with decisions regarding treatment. Genomic testing can help predict how aggressively a prostate cancer might behave and how likely it is to advance and metastasize.
Genetic testing for prostate cancer is indicated in the following circumstances: early onset of prostate cancer, high-risk or very high-risk (aggressive) prostate cancer, regional spread or metastatic prostate cancer, in patients with multiple cancers that include prostate cancer (e.g. prostate cancer and male breast cancer), in prostate cancer patients who have family members with prostate, breast, ovarian, colorectal or pancreatic cancer, and in patients with intraductal prostate cancer histology.
The most common mutations found in prostate cancer are the BRCA2 mutation, which 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). Because of this predisposition to mutation resulting from impaired DNA repair, patients with Lynch syndrome have increased risk not only of colorectal cancers, but a host of other cancers including prostate cancer.
New Jersey Urology currently uses Myriad’s multigene panel for germline testing to determine the presence of 10 genetic mutations commonly implicated in inherited prostate cancer. Specimens are obtained either through a saliva or blood sample and results are typically available in 2-3 weeks. This panel includes the following genes: BRCA1, BRCA2, MLH1, MSH2, MSH6, PMS2, EPCAM, TP53, NBN, and HOXB13.
HOW IT WORKS
BENEFITS OF GENETIC TESTING
There are numerous advantages of finding out if one has a genetic mutation linked to prostate cancer. It can prompt genetic testing of other family members and if they test positive, they may wish to undergo prostate cancer screening starting at an earlier age than men with no family history. Depending upon the particular mutation, they may also wish to undergo screening for other cancers as well. If the BRCA mutation is discovered, it can prompt genetic testing of female family members, since this mutation, if present, will greatly increase the risk for breast and ovarian cancer and will mandate intensified screening. Germline testing has given rise to the exciting field of precision medicine, individualized and customized treatment strategies with specific medications targeted against the specific mutations, a treatment based upon cancer biology and no longer only cancer histology.