The CNIO participates in a study that defines the most important genes that increase the risk of breast cancer

Genetic inheritance affects the likelihood of developing breast cancer. Some genes are already known to increase the risk of cancer; other genes are suspected, but not to what extent. Clarifying this issue is essential to improve prevention, as it opens the way to more personalized screening and monitoring programs. A large international consortium, which includes the National Cancer Research Center (CNIO), has studied 34 putative susceptibility genes in samples of 113,000 cases and controls of female breast cancer, and their results confirm the importance of nine of them.

The study “defines the most clinically useful genes for inclusion in panels for the prediction of breast cancer risk (…), to guide genetic counseling,” the authors write in the New England Journal of Medicine (NEJM).

This is the most ambitious study to date to shed light on the role of heredity in breast cancer, one of the most common cancers today: one in eight women will have it at some point in her life.

250 researchers from dozens of institutions in more than 25 countries participated in the genetic analysis. A third of the samples were analyzed at the CNIO, with the participation of Javier Benítez, Anna González-Neira and Ana Osorio. Groups from seven other Spanish institutions also participated in the study.

Osorio, from the CNIO Human Genetics Group, highlights the importance of the information provided by this study in the follow-up of patients with breast cancer and their families. “Genetic tests are already carried out in people with a family history of the disease, but in these tests we can only analyze genes that we are sure that affect risk. Now we have more information, and we can improve the genetic counseling of patients and their families ”, says the CNIO researcher.

Low and moderate risk genes

It has been known for some time that the risk of developing breast cancer depends in part on genetic inheritance, but determining exactly which genes increase this risk and by how much remains a major challenge.

The genes that confer high risk when they mutate, BRCA1 and BRCA2, were already identified in the mid-1990s. Having mutations in these genes confers a cumulative risk of about 70% of developing breast cancer by the age of 80, and a 40% and 20% risk of developing ovarian cancer for carriers of BRCA1 and BRCA2 mutations, respectively. It was this strong effect that allowed us to identify these genes in families with a high incidence of cancer.

Today, genetic diagnosis alerts the relatives of many patients, who can then act in the very early stages of cancer or even prevent its appearance. But BRCA genes explain only a small part of all cases. In the vast majority of cases, genes that confer a lower risk are involved and that can interact with each other or with other genetic and environmental factors, which can modify the risk.

In recent years, several studies have identified dozens of these candidate genes that increase breast cancer risk to some degree, but these studies were conducted with relatively few patients and their results were inconclusive. The aim of the now published study was to improve this knowledge by precisely determining which genes are involved and to what extent they affect the risk of developing which tumor subtype.

“Genetic tests for breast cancer susceptibility are widely used, but for many genes the evidence of association with breast cancer is weak,” the authors write in NEJM, adding that the risk estimates are imprecise and that cancer subtype-specific risk estimates are completely missing.

“The most clinically useful genes”

The study is the result of the European BRIDGES project (Risk of breast cancer after diagnostic genetic sequencing), in which the CNIO participates. The study was based on the analysis of 34 known or suspected breast cancer susceptibility genes in DNA samples from 60,400 women who had developed breast cancer and 53,400 healthy women.

The results point to nine genes for which there is strong evidence of their involvement in the disease: ATM, BRCA1, BRCA2, CHEK2, PALB2, BARD1, RAD51C, RAD51D and TP53. For some of these genes, this was already known, but for others, such as RAD51C and D and BARD1, their involvement was not as well established. For all genes, more precise risk estimates can now be calculated, and these estimates are tailored for each tumor subtype.

On the other hand, the study shows that a dozen of the genes that have been used so far in some tests “are not indicative of an increased risk” of breast cancer and, therefore, should not be taken into account, at least in this moment, in risk estimates.

However, the authors remind us that the likelihood of developing breast cancer is not determined solely by genes. Other risk factors such as age, hormonal background, and environmental factors also play a role, which in turn are influenced by genetic background.

“In fact”, points out González-Neira, Head of the Human Genotyping Unit – CEGEN of the CNIO, “we have already been working on mathematical models that integrate current knowledge about all these factors and their interaction, which allow us to provide a good estimation of risk adjusted for each woman and thus individualize clinical management ”.

The ultimate goal is to improve prevention with much more personalized screening programs than those currently available. The implementation of these precision medicine protocols in breast cancer will improve early diagnosis and reduce morbidity and mortality rates from this disease.

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This project is funded by the European Union’s Horizon 2020 Research and Innovation Program (BRIDGES), the Wellcome Trust and Cancer Research UK. In the CNIO group, by the Ministry of Science and Innovation of Spain and the Carlos III National Institute of Health.

Reference article: Breast Cancer Risk Genes: Association Analysis in Over 113,000 Women. Leila dorling et al (NEJM, 2020). DOI: 10.1056 / NEJMoa1913948