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The contribution of BRCA1 and BRCA2 to inherited breast cancer was assessed by linkage and mutation analysis in 237 families, each with at least four cases of breast cancer, collected by the Breast Cancer Linkage Consortium. Families were included without regard to the occurrence of ovarian or other cancers. Overall, disease was linked to BRCA1 in an estimated 52% of families, to BRCA2 in 32% of families, and to neither gene in 16% (95% confidence interval [CI] 6%-28%), suggesting other predisposition genes. The majority (81%) of the breast-ovarian cancer families were due to BRCA1, with most others (14%) due to BRCA2. Conversely, the majority of families with male and female breast cancer were due to BRCA2 (76%). The largest proportion (67%) of families due to other genes was found in families with four or five cases of female breast cancer only. These estimates were not substantially affected either by changing the assumed penetrance model for BRCA1 or by including or excluding BRCA1 mutation data. Among those families with disease due to BRCA1 that were tested by one of the standard screening methods, mutations were detected in the coding sequence or splice sites in an estimated 63% (95% CI 51%-77%). The estimated sensitivity was identical for direct sequencing and other techniques. The penetrance of BRCA2 was estimated by maximizing the LOD score in BRCA2-mutation families, over all possible penetrance functions. The estimated cumulative risk of breast cancer reached 28% (95% CI 9%-44%) by age 50 years and 84% (95% CI 43%-95%) by age 70 years. The corresponding ovarian cancer risks were 0.4% (95% CI 0%-1%) by age 50 years and 27% (95% CI 0%-47%) by age 70 years. The lifetime risk of breast cancer appears similar to the risk in BRCA1 carriers, but there was some suggestion of a lower risk in BRCA2 carriers <50 years of age.

In Western Europe and the United States approximately 1 in 12 women develop breast cancer. A small proportion of breast cancer cases, in particular those arising at a young age, are attributable to a highly penetrant, autosomal dominant predisposition to the disease. The breast cancer susceptibility gene, BRCA2, was recently localized to chromosome 13q12-q13. Here we report the identification of a gene in which we have detected six different germline mutations in breast cancer families that are likely to be due to BRCA2. Each mutation causes serious disruption to the open reading frame of the transcriptional unit. The results indicate that this is the BRCA2 gene.

BACKGROUND-Ovarian clear-cell and endometrioid carcinomas may arise from endometriosis, but the molecular events involved in this transformation have not been described.

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No more than Ϸ30% of hereditary breast cancer has been accounted for by mutations in known genes. Most of these genes, such as BRCA1, BRCA2, TP53, CHEK2, ATM, and FANCJ/BRIP1, function in DNA repair, raising the possibility that germ line mutations in other genes that contribute to this process also predispose to breast cancer. Given its close relationship with BRCA2, PALB2 was sequenced in affected probands from 68 BRCA1/BRCA2-negative breast cancer families of Ashkenazi Jewish, French Canadian, or mixed ethnic descent. The average BRCAPRO score was 0.58. A truncating mutation (229delT) was identified in one family with a strong history of breast cancer (seven breast cancers in three female mutation carriers). This mutation and its associated breast cancers were characterized with another recently reported but unstudied mutation (2521delA) that is also associated with a strong family history of breast cancer. There was no loss of heterozygosity in tumors with either mutation. Moreover, comparative genomic hybridization analysis showed major similarities to that of BRCA2 tumors but with some notable differences, especially loss of 18q, a change that was previously unknown in BRCA2 tumors and less common in sporadic breast cancer. This study supports recent observations that PALB2 mutations are present, albeit not frequently, in breast cancer families. The apparently high penetrance noted in this study suggests that at least some PALB2 mutations are associated with a substantially increased risk for the disease.DNA repair ͉ FANCN ͉ Fanconi anemia ͉ hereditary predisposition T he presence of a family history is the most important predisposing factor for development of breast cancer. Among the genes known to be linked to familial breast cancer, BRCA1, BRCA2, CHK2, TP53, and ATM all participate in DNA damage responses (1), suggesting that familial breast cancer is, at least partly, a consequence of impaired genome stability control. PALB2 is a recently identified BRCA2-interacting protein, and a high fraction of each protein interacts with the other (2). Their association is essential for BRCA2 anchorage to nuclear structures and for its function in double strand break repair (DSBR) by homologous recombination (HR). Furthermore, introduction of PALB2 siRNAs sensitized cells to mitomycin C like BRCA2 siRNA (2). PALB2-depleted cells, therefore, display a Fanconi anemia (FA)/ BRCA2-deficient phenotype (3).Recent evidence shows that PALB2 is, in fact, another FA gene (known as FANCN), and that FANCN disease resembles FA arising from biallelic BRCA2 mutations in that the affected children are prone to develop embryonal tumors (medulloblastoma, Wilms tumor) and experience early bone marrow failure (4, 5). In other respects, FA-N cases have a typical FA phenotype. Their cells reveal increased chromosome breakage after interstrand cross-linking agent exposure, and these patients reveal growth retardation and various congenital malformations (4, 5). It is unclear why a different cancer predisposition phenotype exists in FA c...

We have identified four mutations in each of the breast cancer-susceptibility genes, BRCA1 and BRCA2, in French Canadian breast cancer and breast/ovarian cancer families from Quebec. To identify founder effects, we examined independently ascertained French Canadian cancer families for the distribution of these eight mutations. Mutations were found in 41 of 97 families. Six of eight mutations were observed at least twice. The BRCA1 C4446T mutation was the most common mutation found, followed by the BRCA2 8765delAG mutation. Together, these mutations were found in 28 of 41 families identified to have a mutation. The odds of detection of any of the four BRCA1 mutations was 18.7x greater if one or more cases of ovarian cancer were also present in the family. The odds of detection of any of the four BRCA2 mutations was 5.3x greater if there were at least five cases of breast cancer in the family. Interestingly, the presence of a breast cancer case <36 years of age was strongly predictive of the presence of any of the eight mutations screened. Carriers of the same mutation, from different families, shared similar haplotypes, indicating that the mutant alleles were likely to be identical by descent for a mutation in the founder population. The identification of common BRCA1 and BRCA2 mutations will facilitate carrier detection in French Canadian breast cancer and breast/ovarian cancer families.

BACKGROUND The purpose of this investigation was to determine if there are pathobiologic differences between BRCA1‐related and BRCA2‐related hereditary breast cancer (HBC) and non‐HBC. METHODS On the basis of linkage to chromosomes 17q or 13q and/or the presence of ovarian and male breast cancer, HBC families were classified as either “BRCA1‐related” (26 families, 90 breast cancer pathology cases) or “Other” (26 families, 85 cases), in which most BRCA2 cases were likely to reside. Cases were compared with 187 predominantly non‐HBC cases. Tumors were assessed for histologic type, grade, and ploidy and S‐phase fraction by quantitative DNA flow cytometry. Clinical presentation and available follow‐up data were obtained. RESULTS BRCA1‐related and Other HBC patients each presented at lower stage (P = 0.003) and earlier age than non‐HBC patients (mean, 42.8 years and 47.1 years vs. 62.9 years, P < 0.0001). Compared with non‐HBC, invasive BRCA1‐related HBC had a lower diploidy rate (13% vs. 35%; P = 0.002), lower mean aneuploid DNA index (1.53 vs. 1.73; P = 0.002), and strikingly higher proliferation rates (mitotic grade 3; odds ratio [OR] = 4.42; P = 0.001; aneuploid mean S‐phase fraction 16.5% vs. 9.3%, P < 0.0001). Other HBC patients, including patients in two BRCA2‐linked families, had more tubular‐lobular group (TLG) carcinomas (OR = 2.56, P = 0.007). All trends were independent of age. A nonsignificant trend toward better crude survival in both HBC groups was age‐ and stage‐dependent. Compared with Other HBC, BRCA1‐related HBC patients had fewer recurrences (P = 0.013), a trend toward lower specific death rates, and fared no worse than breast cancer patients at large. Other HBC patients, despite neutral prognostic indicators, fared worse. CONCLUSIONS BRCA1‐related HBCs are more frequently aneuploid and have higher tumor cell proliferation rates compared with Other HBC. Despite these adverse prognostic features, BRCA1‐related HBC patients have paradoxically lower recurrence rates than Other HBC patients. The excess of TLG cancers in the “Other” HBC group may be associated with BRCA2 linkage. Cancer 1996; 697‐709.