PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene

Abstract

PALB2 interacts with BRCA2, and biallelic mutations in PALB2 (also known as FANCN), similar to biallelic BRCA2 mutations, cause Fanconi anemia. We identified monoallelic truncating PALB2 mutations in 10/923 individuals with familial breast cancer compared with 0/1,084 controls (P = 0.0004) and show that such mutations confer a 2.3-fold higher risk of breast cancer (95% confidence interval (c.i.) = 1.4-3.9, P = 0.0025). The results show that PALB2 is a breast cancer susceptibility gene and further demonstrate the close relationship of the Fanconi anemia-DNA repair pathway and breast cancer predisposition.

Figure 1

PALB2 mutations in familial breast cancer. (a) Abridged pedigrees of ten families with breast cancer with PALB2 mutations. The probands screened for PALB2 mutations are indicated by arrows. Individuals with breast cancer are shown as filled circles, with the age at diagnosis given underneath. Other cancers are indicated beneath the relevant individuals, with age at diagnosis next to the cancer type. Some individuals with cancer were not genotyped either because they were deceased or because they declined to take part in the study. We obtained informed consent from all families, and the research was approved by the London Multicentre Research Ethics Committee (MREC/01/2/18). The PALB2 mutation in each family is given under the proband and in Table 1. BC, breast cancer; PALB2_WT, PALB2 mutation absent. (b) Schematic diagram of the Fanconi anemia–BRCA pathway. The Fanconi anemia core complex consists of eight Fanconi anemia proteins (FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL and FANCM) and is essential for the monoubiquitination and activation of FANCD2 (‘D2’ in the figure) after DNA damage. Activated FANCD2 is translocated to DNA repair foci, where it colocalizes with other DNA damage response proteins, including BRCA2 and RAD51, and participates in homology-directed repair. Shaded proteins are encoded by genes that cause Fanconi anemia. Proteins outlined in blue are encoded by genes that confer susceptibility to breast cancer. BRIP1, BRCA2 and PALB2 are both Fanconi anemia genes and breast cancer susceptibility genes, and they encode proteins functioning downstream of FANCD2.