Every day seems to bring a new story about developments in breast cancer and genetics. Recent advances in gene analysis technology have revolutionized genetic testing for hereditary cancer susceptibility. For nearly 20 years, we have been able to test for the BRCA1 and BRCA2 genes, but now it is possible to analyze large panels of genes and we have multiple laboratories from which to choose. As a result, we now have the capability of testing high risk patients for multiple suspected hereditary cancer predisposition genes simultaneously, for a cost to the patient that is less than or equivalent to former BRCA1/BRCA2 testing alone. In return, this can lead to the identification of clearly defined cancer risks and the establishment of personalized risk management for high-risk patients.
“Gene panels” have been developed not only for high-risk breast cancer patients, but also for families with a plethora of other cancers such as ovarian, colon, uterine, pancreatic and renal cancers. Depending on the family history, a Genetic Counselor can personalize a test and order panels with 6 of the more common breast cancer genes or consider a larger panel with up to 25, 40 or even 61 genes for those families that are more suggestive of hereditary susceptibility and with a multitude of different cancer diagnoses in the family. These panels are providing clinicians the means to now identify more rare cancer gene mutations, which formerly would have been left undiscovered.
Update Testing for negative BRCA1/2 results
Some patients who already had BRCA1/2 testing with a negative result may come for “Update Testing.” For patients tested prior to August 2006, this may simply entail adding the “BART” or rearrangement testing that has become standard practice today. If some additional significant family history exists, patients who already tested negative for BRCA1/2 may choose to look for mutations in other genes. It would be difficult to discuss each gene that can be added to a panel test here, but consider these examples.
- PTEN is a gene that causes Cowden syndrome. Families with PTEN mutation typically have breast, thyroid or endometrial cancers along with a long list of other non-cancerous features. This can include: macrocephaly (large head size), hamartomatous polyps in the intestine, fibrocystic breasts, lipomas, uterine fibroids, or specific vascular malformations. Genetic counselors will typically measure head size and ask about these non-cancerous features when PTEN is suspected.
- Another gene called PALB2 has received a lot of attention lately. It was cloned in 2006 but a recent article in the New England Journal of Medicine showed that PALB2 mutation carriers have a significant risk for breast cancer, about 33-58% lifetime. With a PALB2 mutation, the risk for breast cancer is 6 to 8 times as high for women in their 40s and 50s. PALB2 also causes an increased risk of pancreatic cancer, so we tend to consider in families with cancer of the pancreas.
- CDH1 is associated with lobular breast cancer as well as gastric cancers.
- The Li Fraumeni syndrome is caused by mutations in the TP53 gene. TP53 families tend to have a wide range of tumors including breast cancer, bone and soft tissue sarcoma, brain tumors, adrenocortical tumors and leukemia.
- There are other genes, such as RAD51C or BRIP1, that are known to cause breast and in some families, ovarian cancers.
With many of these genes, the family spectrum of cancers can look like BRCA but are actually caused by other genes. These are just a few examples of other genes that can be tested on a panel. The number of genes will only continue to grow as new discoveries are made. These new panel tests give us better ability to inform families about their risk and use that information to make risk-reducing clinical decisions.
What to expect from multi-gene panel testing
Like other newly developed tests and practices, there are benefits from multi-gene panels but also challenges and limitations that need to be addressed. There can be unexpected findings such as a mutation in one of the genes on the panel that was not suspected. For some of these newer genes, we are still learning about specific cancer risks with a particular gene mutation. Some gene mutations do not have established guidelines for screening, management, or risk reduction. In addition, there are genetic changes, called variants of unknown significance (VUS), that can be identified on any panel test about 1-4% of the time. These VUS are genetic changes that may or may not cause increased cancer risks in the family and can cause some frustration due to the ambiguity. These limitations present unique challenges to consider for families undergoing a panel test versus a single gene test. Therefore, a Genetic Counselor will only recommend a panel test when the benefits appear to outweigh the limitations.
When to see a Genetic Counselor
Genetic Counselors utilize both pertinent medical and family history information to accurately interpret risk of inheritable disease within a family, while possessing the unique ability to assist with the identification of appropriate testing, counseling and communication of information to at-risk patients and their family members. The world of genetic testing continues to evolve rapidly, not only with the advances in laboratory techniques and expanding clinical testing menus, but also with the explosive increase in laboratories offering cancer gene testing. Genetic Counselors specializing in cancer predisposition are committed to staying abreast of these advances in genetic testing as they evolve over time, ensuring optimal patient care and genetic expertise to the entire healthcare team. To locate a Genetic Counselor in your area, please see the National Society of Genetic Counselors website at www.nsgc.org.