New Breast Cancer Gene Discovered in High-Risk Families

While breast cancers are known to run in families, they are rarely a direct result of mutated genes inherited from a parent. In fact, inherited, or hereditary, cases account for only 5 – 10 percent of all breast cancers.

Mutations in the BRCA1 and BRCA2 genes are the most common cause of hereditary breast cancer. Their discovery in the mid-1990s led to the development of genetic tests that have significantly improved screening and prevention of breast and ovarian cancer.

However, while many hereditary breast cancers are explained by mutations in the BRCA genes, many other severely affected families do not carry mutations in these genes, leaving a gap in screening and prevention opportunities.

“We know of about two dozen genes with either a strong or intermediate effect [on breast cancer risk],” Dr. Kenneth Offit, BCRF grantee and cancer genetics expert, said in a CBS2 New York news story.

A study in the August 7 edition of the New England Journal of Medicine reports that another gene, known as PALB2, may be nearly as important as the BRCA genes in breast cancer risk. Mutations in PALB2 were previously linked to inherited breast cancer, but the extent of this effect wasn’t fully understood.  In the article, an international team led by Dr. Marc Tischkowitz at the University of Cambridge, reported that the lifetime risk of breast cancer in a woman with the PALB2 mutation is about 9 times higher than in the general population, less than that for mutations in BRC1 and closer to the risk associated with BRCA2.

“The lifetime risk of breast cancer linked to mutations in PALB2 climbs to 58 percent for those with two or more close relatives with breast cancer diagnosed under age 50,” said genetics expert Dr. Fergus Couch. The risk of developing male breast cancer also increased more than eight-fold in men with the PALB2 mutation.

The good news is that even though PALB2 mutations are very rare, accounting for only 1 to 2 percent of inherited breast cancers, genetic tests that screen for PALB2 mutations are already available. Commenting on the significance of these findings, Dr. Jeffrey N. Weitzel noted that, “While testing for PALB2 and other rare gene variants associated with breast cancer is now included in more comprehensive genetic testing panels, little was known about the actual risks. This new study gives people with a PALB2 mutation much better information on their risk.”

Study investigators emphasize that additional studies are needed to fully explain the risks associated with the PALB2 mutation. Dr. Susan Domchek clarified that, “Although this is a very important study, we need more families involved in this type of work to better define breast cancer risks as well as to define risks of other cancers such as pancreatic cancer, [which was also increased in people with PALB2 mutations].”

“We think of the PALB2 genes as ‘BRCA3’,” said Mary-Claire King of the University of Washington and director of the BCRF New York Breast Cancer Study. “Since 2010, we have been screening PALB2 in all our study participants, and have encountered critical mutations in families with breast cancer. Very interestingly, though, in the New York Breast Cancer Study—all of whose participants are Ashkenazi Jewish breast cancer patients and their families—there are no families at all with cancer-causing mutations in PALB2. We will know more by the time of the BCRF luncheon in October, but at present, it appears that PALB2 is at most a very minor player in the story of inherited breast cancer among Jewish women.”  

BCRF grantees, Jeffrey N. Weitzel, MD (City of Hope, Duarte CA), Susan M. Domchek, MD (University of Pennsylvania, Philadelphia, PA), Mary-Claire King, PhD (University of Washington, Seattle, WA) and Fergus J. Couch, PhD (Mayo Clinic, Rochester, MN) were co-authors on the New England Journal of Medicine report. 

Reference: Breast-Cancer Risk in Families with Mutations in PALB2.  Antoniou, et al., N Engl J Med. 2014 Aug 7;371(6):497-506.