NIHR | Manchester Biomedical Research Centre

Researchers identify a novel type of genetic change resulting in inherited breast cancer

Researchers from NIHR Manchester Biomedical Research Centre have identified a new mechanism which switches off a gene in families affected by breast and ovarian cancer.

The discovery of the mechanism linked to the BRCA1 gene, known as epigenetic silencing, is published in the American Journal of Human Genetics today.

Breast and ovarian cancer are some of the commonest forms of women’s cancer, with over 54,000 diagnosed with breast cancer1 and over 7,000 diagnosed with ovarian cancer each year in the UK2. For the past 20 years, doctors have tested for mutations in high-risk genes, including BRCA1 and BRCA2, alongside other risk factors such as age at first pregnancy and family history to evaluate a person’s breast and ovarian cancer risk.

Currently cancer causing variations in BRCA1 or BRCA2 are identified in around 20% of families with multiple women with early-onset breast and ovarian cancer. Back in 2013, Angelina Jolie was found to carry a variant in the BRCA1 gene associated with her own increased family risk. However for many women the cause of the many cases of breast and ovarian cancer in their families remains unknown.

This new research, funded by Prevent Breast Cancer and NIHR, identifies a new type of inherited gene variation which results in a ‘switching off’ the BRCA1 gene in two families from Greater Manchester with early-onset breast and ovarian cancer.

The variation is found in the 5? untranslated region (5’UTR), which sits in the region just before the beginning of the gene and is not usually tested for by laboratories. Previously breast cancer associated variants have been described inside the BRCA1 gene and this is the first time researchers have identified that variants outside the gene can result in breast cancer and the mechanism called epigenetic silencing which causes it.

Rebekah, 26 from Manchester, has a family history of early on-set breast cancer and is from one of the two families where this new variation has been identified.

She said: “With such a strong family history of breast cancer, I was always aware that I might be at higher risk. When my mum was told she didn’t carry the BRCA mutation but did have this new genetic change, I decided I needed to know my risk too. Knowledge is power, so I wanted to be on the front foot and have a clear understanding of my own risk of getting breast cancer.

“Thankfully, I tested as negative which means that I don’t have a raised risk. Knowing this has changed my outlook; I’m not going to be spending my life worrying about getting cancer – and any kids I later have won’t be at higher risk, either.”

Rebekah and mum

The research was co-led by Professors Gareth Evans and Bill Newman and Dr Miriam Smith from Manchester University NHS Foundation Trust and The University of Manchester.

Gareth said: “This is an exciting discovery, which has the potential to lead us to learn a lot more about inherited breast and ovarian cancer risk.

“We have found a variation caused by an area that sits just outside of the BRCA1 gene, which has not been linked with an increased cancer risk previously.

“This means that by testing this area outside of the gene and this on/off switch into our existing genetic testing could allow us to identify more women who are at greater risk of developing breast and ovarian cancer and look at preventative treatment and also rule out those at lower risk.”

Lester Barr, Chairman of Prevent Breast Cancer, said: “This research could eventually allow us to offer additional screening to those who have a strong family history of breast cancer but do not have the mutated BRCA gene. This could potentially save thousands of women and men from developing genetic breast cancers.”

Researchers are now examining the exact mechanism as to how the variant switches off the BRCA1 gene and whether other variants in this region have a similar effect which will help to determine which women are at highest risk of breast and ovarian cancer.

1 Cancer Research UK Breast Cancer Statistics (2013 – 2015)  

2 Cancer Research UK Breast Cancer Statistics (2013-2015)