A young patient comes to you anxious about the risk of cancer for herself and her 4 children. She has multiple family members who passed away before age 50 with breast cancer. To her knowledge, none of the affected family members ever underwent genetic testing. Given her strong family history of cancer and your knowledge of the association between BRCA1 and BRCA2 hereditary breast cancer, you order testing for these 2 genes. She is relieved to find out she is negative and continues with routine breast cancer screening. Several years later she is diagnosed with invasive breast cancer. Was her genetic testing wrong? Is there any other testing that should be considered?
The BRCA1 gene was identified in 1994, and BRCA2 followed close behind in 1995. Genetic testing for these two genes was among the first to become clinically available for hereditary breast and ovarian cancer predisposition.1 However, since that time, scientific knowledge in the field of diagnosing and treating inherited cancers has exploded and numerous other very important cancer susceptibility genes have been identified.
Like BRCA1 & 2, these other genes convey an increased risk for the development of cancer. Genes like TP53, STK11, CDH1, PALB2, and PTEN are all associated with a significant increase in breast cancer risk.2 Knowing if a patient has a harmful variant in one of these other cancer genes can dramatically impact patient management and can lead to life saving interventions. In fact, over 50 genes are known or suspected to increase the risk of breast cancer, although information on some of these genes is still emerging3,4, 5 Similar to BRCA1 and BRCA2, many of these genes increase risk for other types of cancer as well While BRCA1 and BRCA2 are still the 2 genes most frequently associated with hereditary breast and ovarian cancer, there is significant clinical overlap between hereditary cancer syndromes. Perhaps more than half of all inherited breast cancer can be attributed to a harmful variant in a gene other than BRCA1 or BRCA2. Thus, if a history is suggestive of a hereditary breast and/or ovarian cancer syndrome, limiting testing only to BRCA1 and BRCA2 will miss a significant proportion of at-risk patients.6 7.
So, what is the best approach when a patient’s personal and/or family history suggest a hereditary cancer syndrome? The approach to testing may differ depending on the individual situation, however, it is always important to gather as much information as possible about the patient’s personal and family history of cancer. Knowing the types of cancer in the family as well as the age of onset can provide valuable clues regarding the most appropriate testing. Although it is best to start testing with the closest affected family member, if they are not available, genetic testing for the unaffected family members can still be helpful.
Many laboratories that do hereditary cancer testing offer multi-gene panels. These panels evaluate many different hereditary cancer-predisposition genes at once and can be an efficient approach to testing. They are most useful for patients with a personal or family history of cancer that does not clearly point to 1 specific cancer syndrome. Multi-gene panels can also identify patients with hereditary cancer predisposition when the clinical suspicion remains high despite a negative result on a single-gene/syndrome genetic test. 8
Many options are available for hereditary cancer testing, and choosing the most appropriate test can be confusing. Quest Diagnostics has Genetic Counselors to assist in understanding the various options for testing. You can also find a clinical Genetic Counselor in your area by going to www.NSGC.org. Genetic Counselors are healthcare professionals with extensive training and knowledge in the field of genetics, including inherited cancer.
So, thinking back to the fictitious patient in our original scenario, since variants in many different hereditary cancer genes, not just BRCA, could give the same clinical picture, additional testing might be helpful. This information would be important for both your patient, her children and other family members. To learn more about various hereditary cancer testing, you can visit www.questhereditarycancer.com, or healthcare providers can call 1.866.GENE.INFO (1.866.436.3463) and speak to our Genomics Client Service Specialists or Genetic Counselors.
- NCCN Guidelines Version 1.2022 Genetic/Familial High-risk Assessment: Breast, Ovarian, and Pancreatic
- Himes, D et al. Hereditary cancer syndrome recognition and testing: Beyond BRCA, The Journal for Nurse Practioners. 2020; (16): 517-522
- Wendt C, Margolin S. Identifying breast cancer susceptibility genes - a review of the genetic background in familial breast cancer. Acta Oncol. 2019 58(2):135-146. doi. 10.1080/0284186X.2018.1529428. Epub 2019 Jan 3. PMID: 30606073.
- Baxter, JS., Leavy, OC., Dryden, NH. et al. Capture Hi-C identifies putative target genes at 33 breast cancer risk loci. Nat Commun 2018; 9, 1028 . https://doi: 10.1038/s41467-018-03411-9
- Suszynska M, Klonowska K, Jasinska AJ, Kozlowski , et al.. Large-scale meta-analysis of mutations identified in panels of breast/ovarian cancer-related genes - Providing evidence of cancer predisposition genes. Gynecol Oncol. 2019 153(2):452-462. doi. 10.1016/j.ygyno.2019.01.027, Epub 2019 Feb 4. PMID: 30733081.
- Wong, ESY, Shekar, Sandhya, Met-Domestici,Marie, et al. Inherited breast cancer predisposition in Asians: multigene panel testing outcomes from Singapore, NPJ Genom Med. eCollection 2016,; 1: 15003 doi: 10.1038 PMID: 29263802