There are seventy-two previously unknown gene mutations that lead to the development of breast cancer, according to a new study by a major international collaboration involving hundreds of researchers around the world, including a co-investigator from the Department of Epidemiology at the University of Washington’s School of Public Health.
Of these gene mutations, reported Monday in the journals Nature and Nature Genetics, 65 are common variants that make women susceptible to breast cancer. The other seven variants predispose women to a particular type of breast cancer known as estrogen-receptor-negative breast cancer - the subset of cases that do not respond to normal hormonal therapies, such as the drug tamoxifen.
The newly identified risk factors nearly double the number that are already known, bringing the total number of known variants that influence breast cancer to roughly 180.
The inherited component of breast cancer is caused by complex interactions between many genetic variants. For example, rare variants in genes such as well-known BRCA1 and BRCA2, confer a high risk of the disease when they contain mutations, while other more common variants confer only a small risk.
The risk variants identified in the two studies are common: some are carried by one woman in a hundred, others are carried by more than half of all women. By themselves, the risks inherent in each variant are minimal; however, because they are common and their effects multiply, the combined effect is significant.
“If you build a risk prediction model by including all previously known variants and these novel genetic variants involved in breast cancer risk, you find that women in the top one percent of the distribution have a three-and-a-half-fold risk of developing breast cancer compared to the population average,” said Sara Lindstrom, assistant professor at the University of Washington, who co-led the investigation and co-authored both papers.
Even larger differences in risk can occur when the genetic variants are coupled with other hormonal and lifestyle factors that influence breast cancer risk.
The findings are a result of work by the OncoArray Consortium, a huge international team involving 550 researchers across six continents. In total, they analyzed genetic data from 275,000 women, of whom 146,000 had been diagnosed with breast cancer.
“This study shows for the first time that many of the genes we believe are targets for these identified genetic variants that influence breast cancer risk are also the genes that are altered in breast tumors,” Lindstrom says.
In other words, the inherited risk of developing breast cancer is linked to the DNA mutation that takes place in the cancer cells once the cancer has developed.
Clear patterns in the genetic variants may help uncover why some women are more at risk of developing breast cancer and which genes are involved. Researchers believe that these findings may inform improved risk prediction and lead to more effective preventive interventions and treatments.