New Breast Cancer Genes May Identify Women Who Can Benefit From Enhanced Screening Interview with:

Fergus J. Couch, Ph.D. Zbigniew and Anna M. Scheller Professor of Medical Research Chair, Division of Experimental Pathology Department of Laboratory Medicine and Pathology Mayo Clinic Rochester, MN 55905

Dr. Couch

Fergus J. Couch, Ph.D.
Zbigniew and Anna M. Scheller Professor  of Medical Research
Chair, Division of Experimental Pathology
Department of Laboratory Medicine  and Pathology
Mayo Clinic
Rochester, MN What is the background for this study? What are the main findings?

Response: The main finding is that RAD51D, BARD1, and MSH6 can now be included in the list of moderate risk breast cancer genes. In contrast, other genes such as MRE11A and RAD50 do not increase risk of breast cancer. In addition, we provide initial estimates of the level of breast cancer risk associated with mutations in the genes that cause breast cancer. The “new” breast cancer genes may now be useful for identifying women who can benefit from enhanced screening. These new data will need to be considered by the National Comprehensive Cancer Network (NCCN) which provides guidelines for clinical management of individuals with mutations in cancer predisposition genes. These results will also be useful for identifying members of families who are at increased risk of breast cancer. Why did you choose to study this particular question?

Response:  Many of the genes on commercial hereditary cancer clinical genetic testing panels do not have defined roles in breast cancer. In short, the involvement of several of the genes in breast cancer susceptibility has not been determined and for other genes we do not have accurate estimates of the level of risk associated with pathogenic mutations. Using a large clinical testing dataset from Ambry Genetics we sought to define the genes involved in breast cancer and to provide estimates of cancer risk for each of the genes that do predispose to breast cancer. Were you surprised by any of the findings–why or why not?

Response: We were able to confirm the involvement of genes such as BRCA1, BRCA2, CHEK2, ATM, and PALB2. That was not surprising. However, we somewhat unexpectedly forund that BARD!, RAD51D, and MSH6 are moderate risk breast cancer genes. We also ruled out several genes such as RAD50 and MRE11A as breast cancer genes. These have been thought to have a role in breast cancer for some time, so it is a surprise to find that they are not involved. How do these findings add to what is already known in this area?

Response: As noted above, we now have extra genes that predispose to breast cancer in the population. These should be useful for testing of families and may prove useful for selecting women who can benefit from better screening for cancer using MRI. Excluding of the genes that are not involved in breast cancer is also important because women found to carry mutations in these genes should not be using the mutations to drive their clinical management. Do you think inclusion of low penetrance/moderate-risk genes on multigene panels provides clinically useful information for patients and their families, or might it sow confusion or have other drawbacks.

Response: Inclusion of the moderate risk genes is important because women can benefit from knowledge about mutations through enhanced screening etc. Low penetrance genes are perhaps more questionable. However, there is still much to learn. For instance it is possible that some genes are low penetrance overall but may be moderate risk for certain breast cancer subtypes. We also are not sure whether other types of mutations such as missense mutations in these various genes have the same effects as truncating mutations. Perhaps in some situations missense mutations can influence risk of breast cancer whereas protein truncating mutations may not. Basically, there is a still a lot to learn about these genes and the only way we can do that is by amassing additional data. We should not remove genes until we are certain that they have no role, as long as the information coming from them is used with caution. What additional research is needed?

Response: We would like to see further validation of these results in other large studies of matched cancer cases and controls. Further efforts are also needed to define cancer risks for genes for the general population and separately for individuals with a family history of breast cancer. Thank you for your contribution to the community.


Couch FJ, Shimelis H, Hu C, Hart SN, Polley EC, Na J, Hallberg E, Moore R, Thomas A, Lilyquist J, Feng B, McFarland R, Pesaran T, Huether R, LaDuca H, Chao EC, Goldgar DE, Dolinsky JS. Associations Between Cancer Predisposition Testing Panel Genes and Breast Cancer. JAMA Oncol. Published online April 13, 2017. doi:10.1001/jamaoncol.2017.0424

Note: Content is Not intended as medical advice. Please consult your health care provider regarding your specific medical condition and questions.

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Last Updated on April 18, 2017 by Marie Benz MD FAAD