Sixty-five new genetic risk markers for breast cancer discovered

Ever since the wide media attention for Angelina Jolie's decision to have her breasts removed preventively, the genetic background of breast cancer has more or less been general knowledge. Mutations in the "breast cancer genes" BRCA1 and BRCA2 dramatically increase* the risk for breast cancer. However, they are very rare and account only for a small portion of breast cancer cases.

"However, there is a multitude of further genetic variations, each of which on its own has only little impact on the breast cancer risk," said Hermann Brenner from the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) in Heidelberg. "But altogether, they can be used to assess the breast cancer risk and, thus, also contribute to better prevention." Epidemiologist Brenner is one of the authors of the present study, which is the largest one worldwide on the genetic causes of breast cancer. Sixty-five further genetic risk markers were identified in the project that was coordinated by researchers from Cambridge and Harvard.

The familial breast cancer risk of women with first-degree relatives who have had breast cancer is about twice as high compared to the general population. The 65 newly identified risk markers are responsible for about four percent of this familial risk. Together with the about 100 genetic risk markers that are already known, an estimated 18 percent can be accounted for.

"In order to be able to predict each woman's individual breast cancer risk more accurately in the future, we want to include these genetic markers in model calculations, together with known risk factors," said DKFZ's Jenny Chang-Claude, who also collaborates in the study. "For example, the genetic risk factors that are known today already make it possible to identify women with an unfavorable risk profile; their risk of developing breast cancer is three and a half times higher than in the general population. Breast cancer screening programs and prevention measures can be individually adjusted based on these risk profiles."

It was a study of superlatives: It included DNA analyses of 256,000 women in total; about half of them suffered from breast cancer. About 90 percent of the participants were from Europe, the U.S.A. and Australia, and about 10 percent from Southeast Asia.

The investigators examined 11.8 million minute genetic variations in search for a possible link with the risk of developing breast cancer. These variants, which differ from each other only in a single DNA building block, are called single nucleotide polymorphisms, or SNPs. Based on the distribution of suspicious SNPs, the researchers were able to identify 65 DNA regions that are very likely to contribute to the breast cancer risk.

Studies of this scale are necessary in order to facilitate statistically ascertained statements about the individual SNPs. Until now, prior studies have focused chiefly on genetic variants that have a minimum prevalence in the population while usually showing only weak links to the breast cancer risk. Further studies will investigate more genetic variations that are less common but are associated with a higher disease risk. This also requires very large numbers of participants that can only be achieved in large international networks. The majority of the 65 newly discovered genetic risk markers are not located in the protein-coding regions of DNA but in so-called regulatory elements: These are genomic segments that are involved in the regulation of genes that can be located at some distance from them. Using computer simulations, the researchers discovered that most of these regulatory elements control cellular processes that are already known to be linked to the development of breast cancer.

*Experts estimate that in Germany approximately 65-75% of women with BRCA1 mutation and 45-65% of women with BRCA2 mutation will develop breast cancer before the age of 70 years.

Kyriaki Michailidou et al: Association analysis identifies 65 new breast cancer risk loci. Nature 2017, DOI: 10.1038/nature24284

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