72 previously unknown gene mutations that lead to the development of breast cancer have been discovered by a major international collaboration of researchers from roughly 300 institutions.

Among the new variants, 65 are common ones that predispose to breast cancer. A further 7 specifically predispose to oestrogen-receptor negative breast cancer, which is a subset of cases that do not respond to hormonal therapies, such as the drug tamoxifen.

No single gene mutation causes breast cancer. Rather, it results from complex interactions between a large number of genetic variants and our environment.

The inherited component of breast cancer risk is due to a combination of rare variants in genes such as BRCA1 and BRCA2 that confer a high risk of the disease, and many more common genetic variants that each cause only a small risk. The newly identified risk regions nearly double the number that are already known, thereby bringing the number of known common variants associated with breast cancer to around 180.

Clear Genetic Patterns

The results are from work by the OncoArray Consortium, a massive effort involving 550 researchers from six continents. In all, they analyzed genetic data from 275,000 women, of whom 146,000 had been diagnosed with breast cancer.

“These findings add significantly to our understanding of the inherited basis of breast cancer. As well as identifying new genetic variants, we have also confirmed many that we had previously suspected. There are some clear patterns in the genetic variants that should help us understand why some women are predisposed to breast cancer, and which genes and mechanisms are involved,"

said one of the lead investigators on the study, Professor Doug Easton from the University of Cambridge.

The researchers combined epidemiological data with other data from breast tissue to make predictions of the target genes that were plausible in the large majority of cases. In addition, they showed for the first time that these genes are often the same as those that are altered in breast tumours - when a tumour develops, the DNA within the cancer cells themselves mutates.

“Given the size of these studies, we expected that we would find a lot of new breast cancer risk variants, but the studies tells us a lot more about which genes are involved, revealing many previously unsuspected genes and genetic mechanisms underlying breast carcinogenesis. This should provide guidance for a lot of future research,"

said Professor Peter Kraft of the Harvard TH Chan School of Public Health.

Estrogen Receptor Positive Breast Cancer

The majority of the variants found were not found within genes, but within regions of the genome that regulate the activity of nearby genes. When the researchers looked at the pattern of these genetic regions, they discovered that this differed from that of those regions involved in predisposition to other common diseases.

Around 70% of all cases of breast cancer are estrogen-receptor positive, meaning that the cancer cells have a particular protein (known as a receptor) that responds to the female sex hormone estrogen, enabling the tumour to grow. However, not all cancer cells carry this receptor - these are known as oestrogen-receptor negative.

The studies identified genetic regions specifically associated with either estrogen-receptor positive or estrogen receptor negative breast cancer, underscoring the fact that these are biologically distinct cancers that develop differently.

“These findings may inform improved risk prediction, both for the general population and BRCA1 mutation carriers. A better understanding of the biological basis of oestrogen receptor negative breast cancer may lead to more effective preventive interventions and treatments,"

said Associate Professor Roger Milne (Cancer Council Victoria).

Michailidou, K et al. Association analysis identifies 65 new breast cancer risk loci Nature; 23 Oct 2017; DOI: 10.1038/nature24284

Milne, RL et al. Identification of ten variants associated with risk of estrogen receptor negative breast cancer Nature Genetics; 23 Oct 2017; DOI: 10.1038/ng.3785

Image: Prof David Becker, Wellcome Images

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