Dr. Catalona and his research team have been directly involved in identifying some of the genetic variations known to be associated with prostate cancer, as well as in validating other researchers' discoveries. Dr. Catalona's ongoing major research project through the Specialized Project of Research Excellence (SPORE) aims to identify which genetic mutations indicate if a man is a good candidate for active surveillance - or if he is likely to "fail" active surveillance.
National guidelines and genetic testing
Currently, most prostate cancer national guidelines that address genetic testing do not include the majority of germline genetic mutations known to be associated with prostate cancer. For example, the National Comprehensive Cancer Network (NCCN) guidelines only discuss BRCA1/2 testing.
Research presented at the American Society for Clinical Oncology Annual Meeting found that current guidelines excluded a large proportion of people and families that would benefit from germline genetic testing.1 The study included 199 patients with prostate cancer who tested positive for a germline genetic variant known to be associated with prostate cancer. However, only 63% of those patients would have qualified for genetic testing under current guidelines.
A new consensus guideline on testing in the clinic
The Prostate Cancer International Consensus Conference wrote a consensus guideline earlier this year to recommend how and when genetic testing should be used in the clinic. Their guidelines include recommendations such as considering genetic testing if you have a first-degree relative (father or brother) who was diagnosed with prostate cancer or died of the disease when they were younger. Also, men with first-degree relatives with hereditary breast or ovarian cancer, or Lynch syndrome should consider genetic testing. The consensus states that patients should be part of the shared decision-making for genetic testing, and patients who test positive for BRCA2 and HOXB13 mutations should consider this when determining PSA screening intervals.
The statement considers family history of breast and ovarian cancers, stressing the importance of taking a full family history into account, including medical history of women in the family. Breast and ovarian cancers can be hereditary - and share germline mutations with prostate cancer.
The consensus statement was presented at the Society of Urologic Oncology 2017 AUA Annual Meeting in May.
1 J Clin Oncol 35, 2017 (suppl; abstr 5009)
Genetic Test for Germline Mutations
Unlike "genomic" tests, which look at gene expression in men with newly diagnosed prostate cancer, "genetic" tests look for germline mutations known to be associated with hereditary prostate cancer. Genetic tests may be useful in identifying patients and their relatives who may have more aggressive disease and/or be susceptible to other life-threatening cancers. Commercial "genetic" tests vary in cost from a few hundred to several thousand dollars and are available to any man with prostate cancer.
Some of the mutations the tests look for are DNA repair gene mutations, BRCA1 and BRCA2, Lynch syndrome mutations, HOXB13, and ATM mutations, among others.
DNA repair gene mutations
At least 34 are associated with prostate cancer. Many of these DNA repair mutations cause DNA repair to be less effective than normal.
BRCA1 and BRCA2
BRCA1 and BRCA2 are tumor suppressor genes involved in the repair of DNA damage. They occur very infrequently in the general population, but men who carry mutations in the gene have an increased risk of developing prostate cancer. Men who carry BRCA1 mutations have an approximately 3.8-fold increased risk of developing prostate cancer before age 65, and men younger than 65 who carry a BRCA2 pathogenic mutation have an up to 7.3-fold increased risk in developing prostate cancer. In addition, prostate cancers with BRCA2 mutations are more aggressive.
Lynch syndrome mutations are germline mutations in one of the mismatch repair (MMR) genes. This leads to accumulation of mutations that can lead to cells becoming malignant. Mutation carriers have a 3.2-fold increased risk of developing prostate cancer. For the MMR gene MSH2, the risk is 5.8-fold higher. Lynch syndrome germline mutations predispose to a high lifetime risk of colorectal, upper GI, ovarian and upper urinary tract cancers. Germline gene sequencing can provide a definitive diagnosis.