Genetic testing for breast cancer susceptibility is widely used and part of medical practice. Until recently, testing was performed mainly in patients with a strong family history of cancer and involved a limited number of genes known to be associated with a high risk of cancer or with specific cancer syndromes.
With the advent of affordable sequencing, testing with larger panels of genes has become possible, but for many genes, evidence of an association with breast cancer is weak, underlying risk estimates are imprecise, and reliable subtype-specific risk estimates are lacking.
To better define the set of genes associated with breast cancer risk, the authors designed a panel consisting of 34 known or suspected breast cancer susceptibility genes, including genes provided on commercial panels. Using this panel, the authors conducted large case-control study and sequenced the germline DNA from more than 60,000 women with breast cancer and more than 53,000 controls participating in studies of the Breast Cancer Association Consortium (BCAC). The data were used to estimate the risks of breast cancer overall and tumor subtypes associated with germline protein-truncating variants and rare missense variants in these genes. The German Familial Breast and Ovarian Cancer Consortium coordinated by Professor Rita Schmutzler (Director of the Center for Familial Breast and Ovarian Cancer, University Hopsital Cologne) contributed nearly 30 percent of all familial samples.
The results of this study published in the prestigious New England Journal of Medicine in January 2021 define the genes that are most clinically useful for inclusion on panels for the prediction of breast cancer risk, as well as provide estimates of the risks associated with protein-truncating variants, to guide genetic counseling.
`In the BRIDGES study, funded by the EU Commission, the already known risk genes BRCA1, BRCA2, PALB2, BARD1, RAD51C, RAD51D, ATM and CHEK2 were confirmed. In addition, the study provides evidence for involvement of the genes FANCM, MSH6, and NF1. These genes seem to play a role especially in familial burden and specific tumor subtypes` says Prof. Rita Schmutzler, coordinator of the German Consortium, head of the Center for Familial Breast and Ovarian Cancer at the University Hospital of Cologne and affiliated with the Center for Molecular Medicien Cologne.
Professor Schmutzler, also received the Research Award 2020 from the University of Cologne on January 26, 2021, adds: ´We will use these findings as a basis to offer risk-adapted preventive measures for women who carry mutations in these new genes and thus further expand our clinical risk management strategies. The more genes we find, the more important it is to evaluate them critically to clarify the genetic risk potential. The women who are affected in our study group all receive a detailed consultation and the offer to participate in individual, risk-adapted screening and prevention programs.´
The study was conducted as part of the EU-funded BRIDGES project (Breast Cancer Risk after Diagnostic Gene Sequencing). Prof. Dr. Schmutzler, who co-initiated the study, is the lead investigator for the clinical implementation. The results of the study were published in the prestigious New England Journal of Medicine in January 2021.
Breast Cancer Risk Genes - Association Analysis in more than 1113,00 Women
Breast Cancer Association Consortium, Dorling L., Carvalho S, Allen J, González-Neira A, Luccarini C, Wahlström C, et. al.
N Engl J Med. 2021 Jan 20. doi: 10.1056/NEJMoa1913948. Online ahead of print. PMID: 33471991
Modified Press Release of the "Universitätsmedizin"