Mutations in a gene called PALB2 raise the risk of breast cancer in women by almost as much as mutations in BRCA1 and BRCA2, the genes implicated in most inherited cases of the disease, a team of researchers reported Wednesday.
Previous data had indicated that mutations in PALB2 were linked to breast cancer, and some genetic tests already screen for them. But it had not been clear to what extent these mutations raised a carrier’s odds of developing the disease.
Mutations in PALB2 can make breast cancer up to nine times more likely to develop in women, the researchers report in the current issue of The New England Journal of Medicine.
About 5 to 10 percent of breast cancers are thought to be caused by bad BRCA1 or BRCA2 genes. Beyond those, many other genes are thought to play a role, but how much each one raises risk has not been known, said Dr. Jeffrey Weitzel, a genetics expert at City of Hope Cancer Center in Duarte, Calif.
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The new study on PALB2 shows “This one is serious,” and probably is the most dangerous in terms of breast cancer after the BRCA genes, said Weitzel, one of the study leaders.
It involved 362 members of 154 families with PALB2 mutations. The faulty gene seems to give a woman a 35 percent chance of developing breast cancer by age 70 and an even greater risk if she has two or more close relatives with the disease.
That’s nearly as high as the risk from a faulty BRCA2 gene, Dr. Michele Evans, of the National Institute on Aging, and Dr. Dan Longo, of the medical journal staff, write in a commentary in the journal.
The PALB2 gene works with BRCA2 as a tumor suppressor, so when it is mutated, cancer can flourish.
The breast-cancer risk for women younger than 40 with PALB2 mutation was eight to nine times higher than that of the general population. The risk was six to eight times higher among women 40 to 60 with these mutations, and five times as high among women older than 60.
The scientists were not able to explain why younger women with the mutations were at higher risk.
The data also indicated that women with the PALB2 mutations were slightly more likely to have “triple-negative” breast cancer, a form resistant to hormone treatment, more aggressive and more likely to recur than other subtypes.
How common the PALB2 mutations are isn’t well-known, but it’s “probably more than we thought because people just weren’t testing for it,” Weitzel said. He found three cases among his own breast-cancer patients in the past month alone.
Among breast-cancer patients, BRCA mutations are carried by 5 percent of whites and 12 percent of Eastern European (Ashkenazi) Jews. PALB2 mutations have been seen in up to 4 percent of families with a history of breast cancer.
Men with a faulty PALB2 gene also have a risk for breast cancer that is eight times greater than men in the general population.
Testing for PALB2 often is included in more comprehensive genetic testing, and the new study should give people with the mutation better information on their risk, Weitzel said. Doctors say that people with faulty cancer genes should be offered genetic counseling and may want to consider more frequent screening and prevention options, which can range from hormone-blocking pills to breast removal.
The actress Angelina Jolie had her healthy breasts removed last year after learning she had a defective BRCA1 gene.
The study was funded by many government and cancer groups around the world and was led by Dr. Marc Tischkowitz of the University of Cambridge in England. The authors include Mary-Clare King, the University of Washington scientist who discovered the first breast-cancer predisposition gene, BRCA1.
Dr. Anees Chagpar, director of the breast center at Yale-New Haven hospital, who was not involved in the work, said she was impressed with the study but cautioned that other factors must be considered in evaluating a woman’s risk.
“This has to be tailored to the patients, who may have other mutations and varying family risk,” she said. “With no family history, the increase they found is 35 percent. If you have two or more family members with cancer, they found a risk of 58 percent.”