If many women in a family develop breast or ovarian cancer, genetic tests can clarify whether the risk is hereditary. So far, however, tests have usually only been carried out for changes in two genes that are associated with high risk. Researchers have now identified other gene mutations that are likely to lead to hereditary breast cancer. The results make it possible to assess the risk of the disease more precisely in the future and thus provide a better basis for deciding whether a woman should have her breasts amputated as a precaution or not.
Various gene mutations are known or suspected of increasing the hereditary risk of breast and ovarian cancer. If such a risk variant is detected, the women affected can take part in an early detection program in order to detect possible tumors at an early stage. Depending on the risk, a complete removal of both breasts and possibly the ovaries may also be considered. Previous tests, however, usually only included two high-risk genes, BRCA1 and BRCA2. Other genes have also been linked to an increased risk, but so far the evidence has not been sufficient to be able to estimate the probability of the disease with sufficient accuracy.
Genetic data from more than 100,000 women
Researchers at the international Breast Cancer Association Consortium (BCAC) have now used a large-scale association analysis to investigate which other gene mutations have an influence on the risk of breast cancer. To do this, they analyzed genetic data from more than 60,000 breast cancer patients and over 53,000 control persons from different parts of the world. They focused on 34 genes that were previously suspected of being linked to breast cancer.
From a technical point of view, tests for corresponding variants in these genes have been possible for a long time. “However, the underlying risk estimates were not precise, and there was a lack of reliable subtype-specific analyzes,” explains co-author Natalia Bogdanova. “To better define the genes associated with breast cancer risk, we designed a special panel. The comprehensive association analyzes also enabled us to determine the disease-specific potential of certain gene mutations. “
Various mutations associated with breast cancer
Different types of mutations can contribute to the increased risk of disease. In some cases, errors in the base code of the DNA ensure that the proteins produced according to this blueprint break off prematurely and are shortened, in other cases – with so-called missense mutations – wrong building blocks are built into the proteins. In nine of the 34 genes examined, the researchers found that protein-shortening mutations are significantly associated with breast cancer risk. This also included the already known BRCA1 and BRCA2 genes. In these two and three other genes, missense variants are also possible in rare cases, which are also associated with an increased risk of breast cancer.
6.3 percent of the European breast cancer patients in the study had a protein-shortening variant in one of the nine identified genes. In the control group, such mutations were only found in two percent of women. Missense variants were found in 2.2 percent of European breast cancer patients and 1.4 percent of women in the control group. The corresponding gene variants were found less frequently in Asian study participants, although here too the proportion was higher in breast cancer patients than in control persons.
More precise risk assessment
“The results of the study allow a more precise assessment of the risk of developing breast cancer. This information is very valuable and helps us with advice, especially before risk-reducing operations, ”says Bogdanova’s colleague Tjoung-Won Park-Simon. The results of the study have already been incorporated into the new recommendations of the Mamma Commission of the Gynecological Oncology Working Group.
However, the authors also point out the limitations of their study: “Despite the scope of this study, the evidence of an association with breast cancer risk remains ambiguous for several of the genes analyzed, and even for those genes that showed a clear association with the risk, the Confidence intervals for the risk estimates are wide. ”However, further studies could refine the results in the future. In addition, it should always be noted that the risk of breast cancer depends not only on family background, but also on other genetic factors and lifestyle. “In order to make a reasonable estimate, it is necessary to include this information in risk models,” the authors say.
Source: Breast Cancer Association Consortium, New England Journal of Medicine, doi: 10.1056 / NEJMoa1913948