Breast-Cancer Risk in Families With Mutations in PALB2

ABSTRACTGermline mutations in the BRCA1 and BRCA2 genes confer a marked increase in risk of breast cancer. Loss-of-function mutations have been identified in the PALB2 gene that also increase the risk of breast cancer. PALB2 interacts with BRCA1 and BRCA2 genes. In previous studies, the risk of breast cancer was estimated to be 2 to 4 times higher among carriers of PALB2 loss-of-function mutations as the risk among nonmutation carriers. Prior to the present study, the exact lifetime risk of breast cancer conferred by such mutations was unknown.The aim of this study was to obtain a robust estimate of the breast cancer risk associated with inherited loss-of-function mutations in PALB2. Data were collected for mutation carriers and their relatives from multiple centers worldwide. The risk of breast cancer was determined for 362 members from 154 families with PALB2 loss-of-function mutations A total of 311 women in these families had PALB2 mutations; 229 of these had breast cancer. The age-specific risk of breast cancer for mutation carriers was estimated using a modified segregation-analysis approach that allowed for the effects of inheritance patterns of disease and PALB2 genotype. Mutation carriers were divided into cohorts of women older than 60 years, between 40 and 60 years of age, and younger than 40 years.Compared with the general population, the risk of breast cancer for women who carried the PALB2 mutation was 8 to 9 times higher among those younger than 40 years, 6 to 8 times higher among those 40 to 60 years of age, and 5 times higher among those older than 60 years. The cumulative risk of breast cancer for female PALB2 mutation carriers was estimated to be 14% (95% confidence interval [CI], 9%–20%) by 50 years of age and 35% (95% CI, 26%–46%) by 70 years of age. Breast cancer risk among mutation carriers increased significantly as the birth cohort became more recent (P < 0.001); risk also was affected by other family factors (P = 0.04). By 70 years of age, the absolute risk of breast cancer for a woman who carried the PALB2 mutation ranged from 33% (95% CI, 25%–44%) if she had no family history of breast cancer to 58% (95% CI, 50%–66%) if she had a strong family history (≥2 first-degree relatives with breast cancer at 50 years of age).These data suggest that the level of breast cancer risk for a PALB2 mutation carrier, with or without a family history of breast cancer, is high. This level of risk may justify adding screening for PALB2 mutations to