Women with mutations in the PALB2 gene have, on average, a 1 in 3 chance of developing breast cancer by age 70 years. This is potentially one of the most important genes associated with breast cancer after the BRCA1/2 genes.

In a study run through the international PALB2 Interest Group, a team of researchers from 17 centers in eight countries led by the University of Cambridge analyzed data from 154 families without BRCA1 or BRCA2 mutations, which included 362 family members with PALB2 gene mutations. The effort was funded by the European Research Council, Cancer Research UK, and multiple other international sources. Their findings were published in the New England Journal of Medicine (2014; doi:10.1056/NEJMoa1400382).

Women who carried rare mutations in PALB2 were found to have on average a 35% chance of developing breast cancer by age 70 years. However, the risks were highly dependent on family history of breast cancer, where carriers with more relatives affected by breast cancer were at higher risk. Only a very small proportion of women worldwide carry such mutations and the researchers point out that additional studies are required to obtain precise estimates of mutation carrier frequency in the population.

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PALB2 is known to interact with both BRCA1 and BRCA2 and was first linked with breast cancer in 2007. As is the case for women who carry mutations in BRCA1 or BRCA2, women with PALB2 mutations who were born more recently tend to be at a higher risk of developing breast cancer than those born earlier. The reason why is unclear, but the researchers speculate that it may be related to factors such as later age at first childbirth, smaller families, and better surveillance leading to earlier age of diagnosis.

“Since the BRCA1 and BRCA2 mutations were discovered in the mid-90s, no other genes of similar importance have been found, and the consensus in the scientific community has been that if more exist we would have found them by now. PALB2 is a potential candidate to be ‘BRCA3.’ As mutations in this gene are uncommon, obtaining accurate risk figures is only possible through large international collaborations like this,” said study leader Marc Tischkowitz, PhD, from the Department of Medical Genetics at the University of Cambridge in the United Kingdom.

“Now that we have identified this gene, we are in a position to provide genetic counselling and advice. If a woman is found to carry this mutation, we would recommend additional surveillance, such as MRI breast screening.”

The researchers have developed a clinical test for PALB2. Clinical testing for PALB2 will be available also in certain other diagnostic laboratories worldwide.

There is evidence that cells carrying the PALB2 mutation are sensitive to a new class of drugs known as PARP inhibitors that are currently being trialled in BRCA1/2-related breast cancers. It is possible that these drugs would also work in PALB2-related breast cancer.