Genetic testing: What can I know? What should I know?
August 13, 2015 | by Jeanne Kelley
As genetic testing becomes more sophisticated, doctors and their patients are finding that such tests can lead to the discovery of previously unknown cancer risks. In his practice at City of Hope, Thomas Slavin, M.D., an assistant clinical professor in the Division of Clinical Cancer Genetics, sees the full spectrum of hereditary cancer disorders in adults and children. Here, he discusses the expanded genetic testing options for people at risk for hereditary breast, ovarian and other cancers.
What are some of the latest advancements in genetic testing?
Breast and ovarian cancer patients and family members at risk for hereditary breast and ovarian cancer syndrome are now being offered testing for many more genes outside of the well-known genes BRCA1 and BRCA2. And while there doesn’t appear to be a “BRCA3,” many other genes have been linked to breast and ovarian cancer predisposition. The recent advances in high throughput, cost-effective, next-generation sequencing techniques and the decision by the Supreme Court that genes cannot be patented have combined to form an explosion in hereditary cancer genetics testing.
Many individuals who seek genetic cancer risk assessment are now offered a multigene panel of 15 to 40 genes, available through many different clinical laboratories. However, little is known about many of the genes currently being tested. One could argue that many of the genes on the panel represent a form of clinical research, since only a handful of the genes outside of the high-risk genes, BRCA1 and BRCA2, can be deemed causative of an individual or family’s cancer predisposition. Many of the genes on these panels are moderate- and low-risk cancer genes, some with very poorly understood cancer risks (e.g., MRE11A). While a positive mutation in one of these “other” genes does not cause disease, it may be part of the picture for patients and their families.
What are the results/outcomes of this multigene panel testing?
There’s still much to be learned, but recent studies have shown that adding extra genes to routine testing of individuals who meet national or their insurance criteria for genetic testing (e.g., history of ovarian cancer, strong family history of breast cancer, early-onset breast cancer under age 46, etc.) can increase the chance that the test will be returned positive from around 10 to 15 percent. Therefore, we have learned that only a few extra percent of familial breast and ovarian cancer cases will be even partially explained. At the same time, testing for more genes increases the chances of finding a variant of uncertain significance that may or may not be associated with any cancer risks, and may instead cause worry for the patient and/or their provider.
How does multigene panel testing provide insight to course of treatment?
An important point of inclusion of the low- and moderate-risk genes on today’s current testing panels is that positive mutations in these genes should often not be treated the same as having a mutation in the gene BRCA1 or BRCA2.
For instance, if a woman is age 41 with breast cancer, she would meet the National Comprehensive Cancer Network criteria for genetic counseling and consideration of genetic testing. If testing were completed using a multigene panel and a BRCA1 mutation were found, not only would I be discussing testing other individuals in her family to keep them cancer-free, if the woman’s long-term prognosis was good, I would be discussing her almost 50 percent risk of ovarian cancer and the recommendation to have her fallopian tubes and ovaries removed given the absence of good ovarian screening techniques.
We would also be discussing the pros and cons of bilateral mastectomy versus high-risk surveillance of her remaining breast tissue.
However, if the same woman in the same scenario had a mutation in the gene ATM, we would not be discussing these extreme measures to keep her cancer-free, since the risk for a future breast cancer and/or ovarian cancer may not even be significantly elevated over the average woman’s risk. This is because the mutation in ATM is likely only partially explanatory of the development of early-onset breast cancer in this individual. Other hereditary and environmental factors may be involved.
We will need a paradigm shift among patients and providers who have become comfortable managing patients with mutations in BRCA1 and BRCA2.
What are some of the other benefits of expanded testing?
One benefit of expanded testing may be discovering cancer risks that were previously unknown. For instance, a CHEK2 mutation may increase one’s risk for colon cancer in addition to breast cancer. Therefore, starting colonoscopies earlier with an increased frequency in that individual or other family members found to carry the mutation can be considered.
Also, many families feel comforted by knowing there is at least a partial explanation for their cancer predisposition. In the future, we will likely understand much more about the cancer risks associated with "other" genes.
Overall, medical cancer genetics has always been a complex field, but it may be more complex now than ever. Those who want to learn more about their genetic testing options, even if they previously had BRCA1 or BRCA2 testing or multigene panel testing in the past should seek consultation with a genetics professional in their area to discuss their personal and family history of cancer and to review their testing if they have not done so already.
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