Mutations in the PALB2 gene may be associated with a significant increase in the risk of breast cancer, according to a recent study in TheNew England Journal of Medicine. PALB2 binds to BRCA2-a gene that confers increased lifetime risk of developing breast or ovarian cancer-and likely permits its stable nuclear localization and accumulation.
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Led by researchers at the University of Cambridge, investigators analyzed the risk of breast cancer among 362 members from 154 families who had deleterious deletion, splice, or truncating mutations in PALB2. A modified segregation-analysis approach, allowing for the effects of residual familial aggregation and PALB2 genotype, was used to estimate the age-specific breast cancer risk for mutation carriers.
The risk of breast cancer for female PALB2 mutation carriers, compared with the general population, was 8 to 9 times higher in those younger than age 40, 6 to 8 times higher in those aged 40 to 60 years, and 5 times higher in the women older than age 60. Estimated cumulative risk of breast cancer in women with the mutation was 15% (95% confidence interval [CI], 9 to 20) by age 50 and 35% (95% CI, 26 to 46) by age 70. The risk of breast cancer was also highly influenced by birth cohort (P<0.001) and other familial factors (P=0.04).
By age 70 years, the absolute breast cancer risk for PALB2 female carriers ranged from 33% (95% CI, 25 to 44) among women who had no familial history of breast cancer to 58% (95% CI, 50 to 66) among women who had 2 or more first-degree relatives with cancer at age 50.
The researchers concluded that loss-of-function mutations on the PALB2 gene appear to be an important cause of hereditary breast cancer. They also indicated that the data suggest that the breast cancer risk associated with PALB2 mutations may overlap with that of BRCA2 mutation carriers.
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