London School of Hygiene & Tropical Medicine

The genetic variants are specifically linked to the most common form of breast cancer, known as oestrogen receptor positive or ER positive breast cancer, and provide important insights into how the disease develops.

Scientists believe screening women for all the genetic variants so far identified could eventually pick out those at highest risk of breast cancer and improve strategies for preventing the disease.

The study, published in Human Molecular Genetics, was led by researchers at The Institute of Cancer Research, in collaboration with scientists from more than 130 institutions worldwide, including the London School of Hygiene & Tropical Medicine and the University of Cambridge. The School's Professor Julian Peto led a genome-wide association study that informed the wider research.

The researchers on the global study analysed the DNA of around 86,000 women of European, 12,000 of Asian and 2,000 of African ancestries, around half of whom had breast cancer.

The study's identification of two new genetic risk factors for breast cancer provides important clues about the causes of the disease - implicating a gene called KLF4, which is thought to help control the way cells grow and divide.

Researchers were looking for one-letter differences in DNA code that were more likely to be found in women with breast cancer than those without the disease, using a state-of-the-art genetic technique called 'fine mapping'. They focused on a recently identified hotspot for genetic causes of breast cancer on chromosome 9.

Women with the first genetic variant identified, called rs10816625, were 12% more likely to develop breast cancer than women without, and those with the second variant, rs13294895, were at a 9% increased risk.

The increases in risk were slightly higher - 14% and 11% respectively - for oestrogen receptor positive breast cancer, but there was no association with oestrogen receptor negative forms of the disease.

The genetic variants are thought to help control the activity of KLF4, despite lying a long distance away from that gene.

Both were associated with increased risk in European women but only one of them, rs10816625, in women of Asian ancestry.

Study leader Dr Nick Orr, from The Institute of Cancer Research, London, said: "Our study zoomed in on an area of our genome that we knew was linked to breast cancer risk, and has identified two new genetic variants that add significantly to our knowledge about the genetic causes of the disease.

"The variants we identified are specifically associated with the most common, oestrogen receptor positive, form of breast cancer. The more genetic risk factors for breast cancer we discover, of which there are currently more than 80, the more accurately we will be able predict who is at risk of getting the disease. Ultimately this will be vital for designing preventative strategies against breast cancer."

The team say that the two new variants uncovered by this study could be factored into potential future screening tools for breast cancer that incorporate all known genetic risk factors for the disease. They also provide important clues to the genetic causes of the most common form of breast cancer and potential leads for the discovery of new treatments.

The next challenges are understanding the biology underpinning the effects of small variations in DNA that can influence a woman's risk of breast cancer. This will help predict individual risk more accurately, improve screening and find better ways to treat and prevent breast cancer.

The research was funded by a range of organisations including Cancer Research UK, Breakthrough Breast Cancer and the European Union.

Publication:

• Nick Orr, Julian Peto et al. Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2, Human Molecular Genetics. Doi: 10.1093/hmg/ddv035