Researchers Report Genetic Testing For Genes Beyond the BRCA1 And BRCA2 Mutations Leaves More Questions than Answers

The discovery of the BRCA1 and BRCA2 genes more than 20 years ago dramatically changed risk assessment, prevention and treatment in families with a high prevalence of breast and/or ovarian cancers.

Subsequent to the discovery of cancer-causing mutations in BRCA1 and 2, large-scale genomics studies have identified other potential susceptibility genes, which when mutated may increase the risk of cancer. Some of these mutations have a clear connection to cancer risk, while the risk conferred by others, referred to as variants of uncertain significance (VUS) are not well understood by scientists or physicians. As technology becomes more widespread, sophisticated and affordable, more extensive scientific analysis can be done on a person’s genetics.  Today, multi-gene panels, some that can analyze as many as 110 genes have been developed. With their increasing use of multiplex panels for cancer screening, there is a concern about the growing list of mutations and their suspected, but unproven association with breast and ovarian cancer risk.

In a study headed by BCRF investigator, Katherine Nathanson and colleagues at from University of Pennsylvania’s Abramson Cancer Center, Mayo Clinic, Memorial Sloan Kettering Cancer Center and City of Hope, researchers found that using an expanded gene panel in high-risk families did not add any clinical benefit beyond the BRCA1/2 screening alone. To evaluate the benefit of expanding the screening panel, the research team analyzed a 180-gene panel consisting of 25 breast/ovarian cancer specific-susceptibility genes, 123 other cancer-susceptibility genes, and 32 genes related to cardiovascular disease risk in 404 individuals in 253 families with breast and/or ovarian cancer. 

“Adding on the additional cancer susceptibility genes to the ‘breast cancer susceptibility’ genes opened up more questions than it answered,” Nathanson said.

Kara Maxwell, BCRF-ASCO Conquer Cancer Foundation grantee and study first author, added that the findings add a new level of complexity to cancer risk counseling in high risk families.  “A patient would now be expected to understand not only that a genetic mutation could exist that may or may not be related to the cancer in their family, but that other genetic variants of  uncertain risk may also be present.” Read more about the study here.

This study was supported in part by BCRF and in addition to Drs. Nathanson and Maxwell, included BCRF investigators Drs. Susan Domchek, Mark Robson, Ken Offit, Fergus Couch, and Jeffrey Weitzel. BCRF has supported research in unraveling the complexity of inherited susceptibility for nearly 20 years. In 2015-16 alone, BCRF funded 24 studies totaling more than $7 million aimed at understanding the role of BRCA, as well as other cancer susceptibility genes.