Partner and localizer of BRCA2 (PALB2) binds to and promotes the localization of BRCA2 to DNA double-strand breaks, enabling proper homologous recombination-mediated DNA repair. Given that mutations in BRCA2 and other breast cancer susceptibility genes account for less than half of familial breast cancers, Robert Winqvist, David Livingston, Hannele Erkko, Bing Xia and colleagues investigated whether PALB2 mutations also increase breast cancer susceptibility.

The authors identified an exonic PALB2 mutation, c.1592delT, that occurred at a significantly higher rate in Finnish BRCA1 and BRCA2 mutation-negative breast cancer families than in controls. Functional testing in cell lines indicated that this mutation produced a truncated protein with true loss of function — decreased binding affinity for BRCA2 and loss of homologous recombination and DNA crosslink repair were observed.

PALB2 c.1592delT mutations were also observed in 18 of 1,918 cases (about 1%) of unselected female breast cancers. This is about fourfold more than the mutation rate in controls, and is noteworthy given that BRCA1 and BRCA2 mutations in Finnish breast cancer together account for 1.8% of cases. Furthermore, many of these 18 cases had a family history of breast and other cancers.

The authors also looked at Finnish prostate cancer cases and found one family in which all male carriers of PALB2 c.1592delT developed prostate cancer (with the exception of one carrier who died early at 52 years of age).

These data argue that PALB2 is a significant breast cancer susceptibility gene that might also be associated with some cases of familial prostate cancer.