When it comes to breast cancer risk, all mutations are not equal, researchers reported Tuesday. The researchers found wide variations in risk for breast and ovarian cancer among women with different mutations of the so-called breast cancer genes, BRCA1 and BRCA2.
Experts in the genetics of cancer have known this for a long time. Everyone has a BRCA1 and a BRCA2 gene. What raises the risk for cancer is a mutation of those genes — and not all mutations raise the risk, either. The mutation has to be one that alters how the gene works.
Now a giant, international collaboration of scientists has started to quantify the risks based on mutation. As suspected, it's not simply having a mutation that matters. It's where the mutation is and how badly it damages the gene that matters.
"Breast and ovarian cancer risks varied by type and location of BRCA1/2 mutations," the team of researchers from around the world write in their report, published in the Journal of the American Medical Association.
The researchers, led by Timothy Rebbeck of the Perelman School of Medicine at the University of Pennsylvania, looked at the DNA of more than 31,000 women who had BRCA1 and BRCA2 mutations.
As expected, the women had a much higher than average risk of breast and ovarian cancer.
"Among BRCA1 mutation carriers, 9,052 women (46 percent) were diagnosed with breast cancer, 2,317 (12 percent) with ovarian cancer, 1,041 (5 percent) with breast and ovarian cancer, and 7,171 (37 percent) without cancer," the team wrote.
"Among BRCA2 mutation carriers, 6,180 women (52 percent) were diagnosed with breast cancer, 682 (6 percent) with ovarian cancer, 272 (2 percent) with breast and ovarian cancer, and 4,766 (40 percent) without cancer."
They were diagnosed much younger than women without the mutations — on average by age 40 for breast cancer patients with BRCA1 mutations, and by age 50 for ovarian cancer.
The researchers note that these are women who chose to be tested, and so they already suspected they might be at high risk, probably because of a relative with cancer.
Women with BRCA1 mutations had a 59 percent lifetime risk of breast cancer and a 34 percent risk of ovarian cancer. Women with BRCA2 mutations had a 51 percent risk of breast cancer and an 11 percent risk of ovarian cancer.
But the risk varied greatly depending on the mutation. Genes are like a recipe - they're a code, and it's written using only four letters: at A,C,T and G that are called nucleotides. These four nucleotides fit together and the pattern dictates whether a cell will make a compound called an amino acid. These amino acids, in turn, mix together to make proteins.
And proteins do all the work in cells.
BRCA1 and BRCA2 are DNA repair genes. They're supposed to find and fix mistakes elsewhere in the DNA code. When they carry mistakes themselves, the repair isn't made, or it's made improperly. And that can lead to cancer.
"There are countless errors that can occur in the DNA," SAYS Dr. Huma Rana, who directs the cancer genetic program at the Dana Farber Cancer Institute.
This study showed worse mistakes were more likely to cause cancer.
For instance, mutations that shortened the gene, making it virtually functionless, raised the risk of breast cancer by 25 percent.
For BRCA2 mutations the risks ranged from 10 percent more to 41 percent more.
Missense mutations were especially bad. Those are bad enough to make a cell produce the wrong amino acid. Missense mutations in one area of the BRCA1 gene called the RING domain raised the risk of breast cancer by 56 percent but a missense mutation on the BRCT domain only slightly raised the risk.
And some mutations raised the risk of one cancer while lowering the risk for the other.
"This study is the first step in defining differences in risk associated with location and type of BRCA1 and BRCA2 mutations," the researchers wrote. An important next step is to figure out just what each mutation does and how it affects an individual woman's risk.
BRCA mutations are among dozens of other genetic mutations that raise the risk of breast or ovarian cancer. About 12 percent of all women will develop breast cancer during their lives, but 55 to 65 percent of women with a BRCA1 mutation will, according to the National Cancer Institute.
About 1 in 400 people have BRCA mutations.
Many women with BRCA mutations get their breasts removed long before any sign of cancer — actress Angelina Jolie was one of them, having her breasts removed at age 37. Women can also take the drug tamoxifen or birth control pills to lower their risks.
Just last month, actor Angelina Jolie announced she'd had her ovaries removed because of her high genetic risk of cancer.