Genetics of Prostate Cancer and Breast Cancer
This month is breast cancer awareness month. Interestingly, breast cancer and prostate cancer have so much in common. Excepting skin cancer, breast cancer is the most common cancer in women; prostate cancer is the most common cancer in men. Breast and prostate are dependent upon the sex hormones estrogen and testosterone, respectively, and one mode of treatment for both cancers is suppression of these hormones with medications.
The incidence of both breast and prostate cancer increase with aging. Breast and prostate cancer are often detected during screening examinations before symptoms have developed: breast cancer is often picked up via screening mammography, whereas prostate cancer is often identified via an elevated or accelerated PSA blood test. Alternatively, breast and prostate cancer are detected when an abnormal lump is found on breast exam or digital rectal exam of the prostate, respectively. Both breast and prostate cells may develop a non-invasive form of cancer known as carcinoma-in-situ—ductal carcinoma-in-situ (DCIS) and high-grade prostate intraepithelial neoplasia (HGPIN), respectively—non-invasive forms in which the abnormal cells have not grown beyond the layer of cells where they originated, often predating invasive cancer by years.
Family history and genetics is relevant to both breast and prostate cancer. Women who inherit BRCA1 and BRCA2 abnormal genes have an increased risk of breast and ovarian cancer; men who inherit the BRCA1 and BRCA2 abnormal genes have an increased risk for prostate cancer. Imaging tests used in the diagnosis and evaluation of both breast and prostate cancers are similar with ultrasonography and MRI commonly used. Surgery, radiotherapy, chemotherapy and hormone therapy are important treatment modalities for both breast and prostate cancer.
How Normal Cells Break Bad into Cancer Cells
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 from environmental toxin exposure 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.
Inherited Mutations Predisposing to Prostate Cancer
Our understanding of “germline” mutations (DNA mutations inherited from one’s mother, father, or both parents) as an important predisposing cause of aggressive prostate cancer has increased dramatically over the past few years. About 10% of prostate cancers are due to inherited germline mutations that have been present in every cell in the body since birth. This is as opposed to “somatic” mutations that occur 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. Inherited germline mutations that increase the risk of these cancers in females—BRCA (BReast CAncer) mutations—also increase the 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); 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 BRCA2.
Genetic and Genomic Testing
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 prostate cancer, aggressive prostate cancer, regional spread or metastatic prostate cancer, multiple cancers including 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 intra-ductal 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, those 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.
There are numerous advantages of finding if one has a genetic mutation linked to prostate cancer. It prompts 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 prompts genetic testing of female family members, since the presence of this mutation will greatly increase the risk for breast and ovarian cancer and mandates intensified screening.
Genetic 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.
Written by Dr. Andrew Siegel