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. PALB2 (for 'partner and localizer of BRCA2') encodes a recently discovered protein that interacts with BRCA2, is implicated in its nuclear localization and stability and is required for some functions of BRCA2 in homologous recombination and double-strand break repair1. In a paper in this issue, we show that biallelic PALB2 mutations are responsible for a subset of Fanconi anemia cases characterized by a phenotype similar to that caused by biallelic BRCA2 mutations2. Prompted by these observations, we investigated whether monoallelic PALB2 mutations confer susceptibility to breast cancer by sequencing the gene © 2007 Nature Publishing Group Correspondence should be addressed to N.R (nazneen.rahman@icr.ac.uk).. AUTHOR CONTRIBUTIONS The study was designed by N.R. and M.R.S. The molecular analyses were performed by S.S., P.K., A.R., S.R., K.S., R.B., T.C., H.J. and S.H. under the direction of N.R. The statistical analyses were performed by D.T., A.E. and L.M. under the direction of D.F.E. The familial collections were initiated by D.G.E. and D.E. and were collected by the Breast Cancer Susceptibility Collaboration (UK). The manuscript was written by N.R. and M.R.S.Note: Supplementary information is available on the Nature Genetics website. COMPETING INTERESTS STATEMENTThe authors declare that they have no competing financial interests. We identified truncating PALB2 mutations in 10/923 (1.1%) independently ascertained individuals with familial breast cancer from separate families compared with 0/1,084 (0%) controls (P = 0.0004) ( Table 1 and Fig. 1a). Nine of the PALB2 mutations were in the 908 families with female breast cancer only (1.0%). One occurred in the 15 families (6.7%) with cases of both female and male breast cancer (P = 0.15). Although this observation requires further investigation, it suggests that PALB2 mutations may confer a higher relative risk of male breast cancer than female breast cancer, and BRCA2 mutations are known to confer a high relative risk of male breast cancer3. One proband with a PALB2 mutation developed melanoma at 47 years of age in addition to breast cancer at 56 years. Apart from this individual, there were no other malignancies other than breast cancer in individuals with PALB2 mutations. Two of four first-degree affected relatives of probands with PALB2 mutations also carried a PALB2 mutation. This pattern of incomplete segregation in affected relatives is typical of s...

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“…According to this model, genetic susceptibility to breast cancer is explained by the effects of BRCA1 and BRCA2 mutations, and the residual familial clustering is explained by the joint multiplicative effect of a large number of genes each of small effect (i.e., by a polygenic component). Direct evidence for the polygenic basis of the residual familial clustering not due to BRCA1 and BRCA2 mutations has more recently been provided by the identification of further loci that confer moderate risks, including mutations in CHEK2, ATM, PALB2, BRIP1 (The CHEK2 Breast Cancer Case -Control Consortium, 2004;Renwick et al, 2006;Seal et al, 2006;Rahman et al, 2007) and the low-risk variants identified through genome-wide or candidate gene association studies Easton et al, 2007;Hunter et al, 2007;Stacey et al, 2007).…”

Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

“…210,211 In addition, germline mutations in RAD51C and RAD51D, more recently shown to interact with the Fanconi pathway 212 as well as RAD51 and the BRCA1 co-factor BARD, have all been associated with predisposition to breast and/or ovarian cancer. [213][214][215] These findings, revealing defects in the Fanconi pathway beyond BRCA1/2 mutations to be associated with cancer risk, advocate disturbances in other Fanconi complex components to be examined with respect to drug sensitivity/resistance as well (see below).…”

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“…Further, genetic linkage analyses failed to identify additional high-penetrance susceptibility genes and the identification of rare variants of genes involved in DNA repair, such as CHEK2, ATM, BRIP and PALB2 in families lacking BRCA mutations (Meijers-Heijboer et al, 2002;Thompson et al, 2005;Rahman et al, 2007;Hollestelle et al, 2010), associated with a moderate risk of disease, can explain only a small portion of familial risk.…”