Four new genes linked to breast cancer risk

An international research team has detected four new genes, the alteration of which may predispose women to breast cancer. Their discovery could lead to better genetic screening tests, improve the monitoring of women with cancer and even open the way to new therapeutic avenues. Current genetic testing for breast cancer only considers a handful of high-risk genes, such as BRCA1, BRCA2 and PALB2. However, these only explain about 10% of the genetic risk. “For the vast majority of women tested who have a family history, we do not find the gene and the mutation responsible for the cancer," says Jacques Simard, researcher at the genomics center of the CHU de Québec-Université Laval (UL) Research Center. "We knew that there are other susceptibility genes. We tried to identify them." Read: Toronto hospital opens up genetic screening to all breast cancer patients To find these rare genetic mutations, the research team analyzed a large number of samples. “To our knowledge, this is the largest study of its kind. It was made possible through the use of data from multiple collaborators in many countries, as well as publicly available data from . . . the UK Biobank,” says Douglas Easton, director of the Center for Genetic Epidemiology of Cancer at the University of Cambridge, For the study, published in Nature Genetics, researchers screened the genetic modifications of all the genes in 26,000 women with breast cancer and compared them to those of 217,000 healthy women. All these women came from eight countries in Europe and Asia. “We cast a wide net to be able to detect the most significant genetic variants,” says Simard. This method allowed him and his colleagues to discern at least four new genes associated with an increased risk of breast cancer. They also found evidence of an association with a dozen other genes at lower risk. Read: Does obesity increase the risk of breast cancer recurrence? “Most of the genetic variants we have identified remain rare in the population, but the risks can be significant for women who carry them," says Simard. For example, alterations in one of these four new genes, MAP3K1, seem to predispose women to a five times higher risk of breast cancer. More research is needed before these four new genes can be used in a clinical setting to refine genetic testing, however. “We need additional data to more precisely determine the cancer risks associated with variants of these genes, to study the characteristics of tumors, and to understand how these genetic effects combine with other lifestyle factors that influence risks of breast cancer,” says Easton. To this end, the research team launched a replication study with an even larger cohort, but also more diverse in terms of age and ethnic origins. “The goal is to integrate our information into a multifactorial risk prediction model, which is already used worldwide. The idea is to combine genomic risk profiles with other known factors, such as family history, hormonal factors and lifestyle habits,” says Simard, who hopes to be able to detect women at high risk in order to give them access to imaging and monitoring screening techniques as early as possible. The discovery of these new genes also provides crucial information on the mechanisms underlying the development of breast cancer, possibly opening the way to new therapeutic targets. “By better understanding the nature of genetic alterations behind a tumor, we can better target potential new treatments,” says Simard, noting that the discovery of variations in the BRCA1 and BRCA2 genes, to which he contributed, led to the development of PARP (poly-ADP-ribose-polymerase) protein inhibitors. This article was translated from French and originally ran in our sister publication Profession Santé.

Four new genes linked to breast cancer risk

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