Germline mutations in BRCA1 and BRCA2 confer high risks of breast and ovarian cancer, but the average magnitude of these risks is uncertain and may depend on the context. Estimates based on multiple-case families may be enriched for mutations of higher risk and/or other familial risk factors, whereas risk estimates from studies based on cases unselected for family history have been imprecise. We pooled pedigree data from 22 studies involving 8,139 index case patients unselected for family history with female (86%) or male (2%) breast cancer or epithelial ovarian cancer (12%), 500 of whom had been found to carry a germline mutation in BRCA1 or BRCA2. Breast and ovarian cancer incidence rates for mutation carriers were estimated using a modified segregation analysis, based on the occurrence of these cancers in the relatives of mutation-carrying index case patients. The average cumulative risks in BRCA1-mutation carriers by age 70 years were 65% (95% confidence interval 44%-78%) for breast cancer and 39% (18%-54%) for ovarian cancer. The corresponding estimates for BRCA2 were 45% (31%-56%) and 11% (2.4%-19%). Relative risks of breast cancer declined significantly with age for BRCA1-mutation carriers (P trend.0012) but not for BRCA2-mutation carriers. Risks in carriers were higher when based on index breast cancer cases diagnosed at <35 years of age. We found some evidence for a reduction in risk in women from earlier birth cohorts and for variation in risk by mutation position for both genes. The pattern of cancer risks was similar to those found in multiple-case families, but their absolute magnitudes were lower, particularly for BRCA2. The variation in risk by age at diagnosis of index case is consistent with the effects of other genes modifying cancer risk in carriers.

Breast cancer exhibits familial aggregation, consistent with variation in genetic susceptibility to the disease. Known susceptibility genes account for less than 25% of the familial risk of breast cancer, and the residual genetic variance is likely to be due to variants conferring more moderate risks. To identify further susceptibility alleles, we conducted a two-stage genome-wide association study in 4,398 breast cancer cases and 4,316 controls, followed by a third stage in which 30 single nucleotide polymorphisms (SNPs) were tested for confirmation in 21,860 cases and 22,578 controls from 22 studies. We used 227,876 SNPs that were estimated to correlate with 77% of known common SNPs in Europeans at r2 > 0.5. SNPs in five novel independent loci exhibited strong and consistent evidence of association with breast cancer (P < 10(-7)). Four of these contain plausible causative genes (FGFR2, TNRC9, MAP3K1 and LSP1). At the second stage, 1,792 SNPs were significant at the P < 0.05 level compared with an estimated 1,343 that would be expected by chance, indicating that many additional common susceptibility alleles may be identifiable by this approach.

Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57–1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628–0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs.

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...