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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PALB2 was recently identified as a nuclear binding partner of BRCA2. Biallelic BRCA2 mutations cause Fanconi anemia subtype FA-D1 and predispose to childhood malignancies. We identified pathogenic mutations in PALB2 (also known as FANCN) in seven families affected with Fanconi anemia and cancer in early childhood, demonstrating that biallelic PALB2 mutations cause a new subtype of Fanconi anemia, FA-N, and, similar to biallelic BRCA2 mutations, confer a high risk of childhood cancer.

Our findings suggest that acquisition of EBV is enhanced by penetrative sexual intercourse, although transmission could occur through related sexual behaviors, such as "deep kissing." We also found that EBV type 1 infection is significantly more likely to result in IM. Overall, the results suggest that a large EBV type 1 load acquired during sexual intercourse can rapidly colonize the B cell population and induce the exaggerated T cell response that causes IM. Thus, IM could, perhaps, be prevented with a vaccine that reduces the viral load without necessarily inducing sterile immunity.

Oligonucleotides labeled with hexachlorofluorescein (hex) have enabled the interaction of the restriction endonuclease EcoRV with DNA to be evaluated using fluorescence anisotropy. The sensitivity of hex allowed measurements at oligonucleotide concentrations as low as 1 nM, enabling K(D) values in the low nanomolar range to be measured. Both direct titration, i.e., addition of increasing amounts of the endonuclease to hex-labeled oligonucleotides, and displacement titration, i.e., addition of unlabeled oligonucleotide to preformed hex-oligonucleotide/EcoRV endonuclease complexes, have been used for K(D) determination. Displacement titration is the method of choice; artifacts due to any direct interaction of the enzyme with the dye are eliminated, and higher fluorescent-labeled oligonucleotide concentrations may be used, improving signal-to-noise ratio. Using this approach (with three different oligonucleotides) we found that the EcoRV restriction endonuclease showed a preference of between 1.5 and 6.5 for its GATATC target sequence at pH 7.5 and 100 mM NaCl, when the divalent cation Ca2+ is absent. As expected, both the presence of Ca2+ and a decrease in pH value stimulated the binding of specific sequences but had much less effect on nonspecific ones.