Breast cancer genetics revealed: 72 new mutations discovered in global study

The genetic causes of breast cancer just got clearer.

Researchers from 300 institutions around the world combined forces to discover 72 previously unknown gene mutations that lead to the development of breast cancer. Two studies describing their work published Monday in the journals Nature and Nature Genetics. The teams found that 65 of the newly identified genetic variants are common among women with breast cancer. The remaining seven mutations predispose women to developing a type of breast cancer known as estrogen-receptor-negative breast cancer, which doesn't respond to hormonal therapies, such as the drug tamoxifen. The new discoveries add to previous research bringing the total number of known variants associated with breast cancer to nearly 180.

Beyond BRCA1 and BRCA2

The international team of 550 researchers across six continents, known as the OncoArray Consortium, included professor Doug Easton of the University of Cambridge, who led the investigation. "Essentially, we used blood samples from a very large number of women (nearly 300,000), about half of whom had had breast cancer," Easton explained in an email. Next, the researchers used the DNA from the samples to look for genetic mutations. "Think of a gene as a very long strand of DNA," said Dr. Otis Brawley, chief medical officer of the American Cancer Society, who was not involved in the research. DNA is made up of nucleic acids, and when a nucleic acid is incorrectly placed along the strand, this is referred to as a genetic mutation, noted Brawley.

Take BRCA1 and BRCA2, two well-known genes that confer a high risk of breast cancer when they contain mutations. There are 125,950 base pairs in the BRCA 1 mutation, noted Brawley. "Think of it as a 125,950 letter word," said Brawley. "A mutation is a misspelling such that the gene cannot code the proper protein." A gene that cannot code the proper protein leads to disease. According to the National Cancer Institute, 55% to 65% of women who inherit a BRCA1 mutation and around 45% of women who inherit a BRCA2 mutation will develop breast cancer by age 70. However, the BRCA1 and BRCA2 risk mutations, which are present in less than 1% of women, explain only a fraction of all inherited breast cancers. The consortium came together, then, to discover the other causes of breast cancer susceptibility -- the additional genetic mutations that can lead to this form of cancer.

Finding the other mutations

The researchers measured DNA at over 10 million sites across the genome, said professor Peter Kraft of Harvard T.H. Chan School of Public Health, a study author. "At each of these sites, we asked whether the DNA sequence in women with breast cancer was different than that in women without," said Kraft. "Because our study was so large, we could detect subtle differences between these two groups of women and be sure these differences were not due to chance." According to Jacques Simard, a study author and professor and researcher at Université Laval, Quebec City, the newly discovered mutations only slightly -- by anywhere from 5% to 10% -- increase a woman's risk of developing breast cancer. But even though, individually, these mutations don't have as big as an effect as BRCA1 and BRCA2 defects, there are many of them, so their "overall contribution is larger," said Easton. An individual woman, then, may have two or more of these common smaller risk gene mutations, and so her risk for developing breast cancer increases due to their combined effects. Kraft noted that "taken together, these risk variants may identify a small proportion of women who are at 3-times increased risk of breast cancer." Women found to have a number of these smaller risk genetic mutations, then, would likely benefit from earlier mammography screening. Simard agreed, noting that it may be time to "adapt" breast cancer screening guidelines based on this information instead of basing mammography guidelines on age alone. By doing so, Simard said, "we will detect a higher number of breast cancers."