Nature Genetics. January 2020

A major international study of the genetics of breast cancer, that kConFab contributed recruited participants blood DNA and clinical data to, has identified more than 350 DNA 'errors' that increase an individual's risk of developing the breast cancer. The scientists involved say these blood DNA errors may influence as many as 190 genes. This work provides the most comprehensive map of breast cancer risk due to these errors (also known as genetic variants) to date. The researchers from 450 departments and institutions worldwide say the findings will help provide the most detailed picture yet of how differences in our blood DNA put some women at greater risk than others of developing breast cancer. The majority of DNA profiles is identical between individuals, but there are some differences or errors, known as genetic variants, and these changes can have a profound effect, increasing an individual's susceptibility to cancer. In this new study, researchers collaborated together to compare the DNA of 110,000 breast cancer patients against that of some 90,000 healthy controls. By looking in much closer detail than was previously possibly, they identified 352 risk variants. It is not yet clear exactly how many genes these target, but the researchers have identified 191 genes with reasonable confidence; less than one in five of these had been previously recognised. We know that most diseases are complex, that no single genetic variant (or DNA error) or gene causes the disease, but rather the combination of a number of them act together to increase the likelihood that an individual will develop a particular disease. Breast cancer is one such example of a complex disease.

Previous Genome-Wide Association Studies (GWAS), which involve comparing the DNA of cancer patients against that of healthy controls, have found around 150 regions of the genome that clearly affect breast cancer risk. Within these regions, researchers know there are one or more genetic changes that affect the risk of developing cancer, but rarely are they able to pinpoint the specific variants (errors) or genes involved. Fine-mapping studies, such as this one, allow scientists to narrow down which variants contributing to the cancer, how they might work and predict which are the genes involved. Of the newly-discovered genetic variants, a third predispose women towards developing hormone-responsive breast cancer, the type of disease found in four out of five breast cancer patients, which respond to hormonal treatments such as tamoxifen. 15% of the genetic variants predispose women to the rarer type, estrogen-receptor-negative breast cancer. The remaining genetic variants play a role in both types of breast cancer. While each genetic variant only increases the risk of developing breast cancer by a very small amount, the researchers say that added together, these will allow them to 'fine tune' genetic testing and give women a much clearer picture of their genetic risk. This will then allow doctors and clinicians to provide advice on the best strategy for reducing their risk and preventing onset of the disease. Professor Doug Easton, from the University of Cambridge, UK and one of the lead researchers on this project, said: "Our work would not have been possible without the help of the 200,000 volunteers who allowed us to study their DNA. It is also testament to the work of hundreds of researchers from all over the world who collaborated on this study."