International study uses genetics to comprehensively map breast cancer risk

A team of scientists from over 450 institutions world wide have mapped the biggest number of genetic variants affecting breast cancer risk ever examined. They suggest that this study will enable them to better understand DNA difference and how it affects breast cancer risk. Scientists from the University of Cambridge were part of the study, which was published in Nature Genetics, a peer-reviewed medical journal, at the beginning of 2020. An abstract can be read on the journal website.

BRCA1 and BRCA2 are two genes that have long been associated with the disease and can be inherited through families. Human DNA has between 20,000 - 25,000 genes which can make it complicated to identify exactly which genes may be likely to cause problems. Genetic variations can be found inside the genes, altering the protein that they code, or outside the genes which can impair their function, making them increase their function or slow it down. They can also make the genes turn off their function completely. In addition, the disease is not caused by a single gene, but by a combination of genes which will act together. This increases the risk of a person developing breast cancer.

Previous studies that have examined the genes’ association with breast cancer have discovered about 150 regions that can be linked with cancer risk, but due to the sheer numbers involved, it can be difficult to find the exact location. This study involved fine-mapping, where the scientists examined a particular region of the genome in order to find genetic markers that are close enough to the gene to cause the genetic trait being examined. Once they find a marker, the scientists examined them closely to predict how they might work and on which genes. This gives them a better idea on how the disease multiplies and how possible treatments might work.

The study compared the DNA of 110,000 patients who had been diagnosed with breast cancer with 90,000 healthy people, through all the institutions which took part. The scientists identified 352 genetic risk variants, but 191 with reasonable confidence. Around 20% had not been identified before. This gave the scientists more genes than ever to work with, including new ones, enabling them to understand better how the disease begins and how it develops. The results from the study also showed how complex the disease can be.

Around 33% of women with the new genetic variants were more likely to develop hormone-responsive breast cancer, which is the most common form. Around 15% would develop the rarer oestrogen-receptor-negative type. The rest would develop a cancer affected by a mix of the two types of genetic actions. The activity of the genes tended to be affected, rather than the gene proteins themselves. The Oestrogen Receptor gene could be affected by 9 different variants, including affecting DNA places where the gene binds and regulates other genes.

These genetic variants do not increase a patient’s breast cancer risk by much, but bringing together all the new genetic variants found enabled the scientists to improve genetic testing and to give women a better picture of their genetic risk. It will also help influence doctors and consultants to find the best treatment to reduce risk as well as delaying or preventing the onset of illness.

Breast cancer is the most common cancer in the UK, affecting 30% of all new female cancer cases, but only 1% of male. Risk factors include old age, family history of close family members getting the disease, environmental factors including air pollution, lifestyle factors including obesity, smoking or drinking alcohol and a lack of exercise. Symptoms include changes in appearance to your breasts, one side being bigger than the other, finding a lump either in the breast or under the arm, changes to breast skin and a pulled-in nipple.

Although there are ongoing challenges to the NHS, if you spot any possible symptoms of breast cancer, then do make an appointment to speak to your GP. Finding cancer at the earliest possible opportunity will improve the effectiveness of treatment.

Fachal, L., et al. Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes. Nature Genetics, 2020

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