Breast-cancer risk in families with mutations in PALB2

Abstract

Background: Germline loss-of-function mutations in PALB2 are known to confer a predisposition to breast cancer. However, the lifetime risk of breast cancer that is conferred by such mutations remains unknown.

Methods: We analyzed the risk of breast cancer among 362 members of 154 families who had deleterious truncating, splice, or deletion mutations in PALB2. The age-specific breast-cancer risk for mutation carriers was estimated with the use of a modified segregation-analysis approach that allowed for the effects of PALB2 genotype and residual familial aggregation.

Results: The risk of breast cancer for female PALB2 mutation carriers, as compared with the general population, was eight to nine times as high among those younger than 40 years of age, six to eight times as high among those 40 to 60 years of age, and five times as high among those older than 60 years of age. The estimated cumulative risk of breast cancer among female mutation carriers was 14% (95% confidence interval [CI], 9 to 20) by 50 years of age and 35% (95% CI, 26 to 46) by 70 years of age. Breast-cancer risk was also significantly influenced by birth cohort (P<0.001) and by other familial factors (P=0.04). The absolute breast-cancer risk for PALB2 female mutation carriers by 70 years of age ranged from 33% (95% CI, 25 to 44) for those with no family history of breast cancer to 58% (95% CI, 50 to 66) for those with two or more first-degree relatives with breast cancer at 50 years of age.

Conclusions: Loss-of-function mutations in PALB2 are an important cause of hereditary breast cancer, with respect both to the frequency of cancer-predisposing mutations and to the risk associated with them. Our data suggest the breast-cancer risk for PALB2 mutation carriers may overlap with that for BRCA2 mutation carriers. (Funded by the European Research Council and others.).

Figure 1. Loss-of-Function PALB2 Germline Mutations in Relation to Functional Domains and Structural Motifs of the PALB2 Protein, and Cumulative Breast-Cancer Risk for Female Mutation Carriers

Panel A is a schematic representation of the PALB2 gene together with all deleterious variants reported in this study, superimposed on the exonic structure of the gene, with functional domains and structural motifs indicated. The number of families with a certain allele is shown in parentheses after the mutation; no such number is given for mutations present only in single families. Numbers in square brackets after functional domains and structural motifs denote amino acid positions. Note that the KEAP1 interaction functional domain is an extended ETGE motif. Panel B shows the mean cumulative risk of breast cancer for female PALB2 mutation carriers and associated confidence intervals.