PALB2 Mutations Confer High Risk of Breast Cancer

The impact of PALB2 mutations on breast cancer risk has been quantified

medwireNews: One in three women carrying a loss-of-function PALB2 mutation will develop breast cancer before the age of 70 years, say researchers who found the risk is even higher for patients who also have a familial history of the disease.

“On the basis of our estimates, the breast-cancer risk for a PALB2 mutation carrier, even in the absence of a family history of breast cancer, would be classified as high according to various guidelines”, say Marc Tischkowitz, from the University of Cambridge in the UK, and co-workers.

“This level of risk may justify adding PALB2 to genetic testing for BRCA1 and BRCA2,” they write in the New England Journal of Medicine.

Of 311 women and 51 men from 154 families with a truncating, splice or deletion PALB2 mutation, breast cancer was detected in 229 of the female and seven of the male participants.

Using the Most Parsimonious Model, women carrying a PALB2 mutation aged 20 to 34 years were around nine times more likely to develop breast cancer than age-matched members of the UK population. The mean relative risk decreased to around eight-fold by the age of 40 years, and five-fold by 65 years.

By age 50 years, women with a mutation had an estimated cumulative risk of breast cancer of 14%, rising to 35% by age 70 years, report Marc Tischkowitz et al.

Men with a PALB2 mutation were calculated to have an 8.3 fold risk of breast cancer compared with the general population, the team adds.

The researchers note that the relative risk of breast cancer was 6.29 times higher in women born in 1960 or after compared with women born before 1940, a phenomenon also reported for carriers of the BRCA1 and BRCA2 Mutations.

Moreover, the likelihood of breast cancer in female PALB2 mutation carriers was significantly altered by their family history of the disease. For example, women with no affected family members had an absolute risk of breast cancer by age 70 years of 33%, whereas the absolute risk was 58% for women whose mother and sister were diagnosed before the age of 50 years.

“[W]omen with loss-of-function mutations in PALB2 should be studied to determine whether enhanced surveillance for breast cancer, in line with that offered to women with mutations in BRCA2, can influence outcomes”, the researchers conclude.

“Risk-reducing surgical options could also be tested.”


Antonious A, Casadei S, Heikkinen T, et al. Breast-cancer risk in families with mutations in PALB2. New Engl J Med 2014; 371: 497–506. DOI: 10.1056/NEJMoa1400382

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