Mutations in known breast cancer susceptibility genes account for a minority of the familial aggregation of the disease. To search for further breast cancer susceptibility genes, we performed a combined analysis of four genome-wide linkage screens, which included a total of 149 multiple case breast cancer families. All families included at least three cases of breast cancer diagnosed below age 60 years, at least one of whom had been tested and found not to carry a BRCA1 or BRCA2 mutation. Evidence for linkage was assessed using parametric linkage analysis, assuming both a dominant and a recessive mode of inheritance, and using nonparametric methods. The highest LOD score obtained in any analysis of the combined data was 1.80 under the dominant model, in a region on chromosome 4 close to marker D4S392. Three further LOD scores over 1 were identified in the parametric analyses and two in the nonparametric analyses. A maximum LOD score of 2.40 was found on chromosome arm 2p in families with four or more cases of breast cancer diagnosed below age 50 years. The number of linkage peaks did not differ from the number expected by chance. These results suggest regions that may harbor novel breast cancer susceptibility genes. They also indicate that no single gene is likely to account for a large fraction of the familial aggregation of breast cancer that is not due to mutations in BRCA1 or BRCA2.
A large number of sequence variants identified in BRCA1 and BRCA2 cannot be distinguished as either disease-causing mutations or neutral variants. These so-called unclassified variants (UVs) include variants that are located in the intronic sequences of BRCA1 and BRCA2. The purpose of this study was to assess the use of splice-site prediction programs (SSPPs) to select intronic variants in BRCA1 and BRCA2 that are likely to affect RNA splicing. We performed in vitro molecular characterization of RNA of six intronic variants in BRCA1 and BRCA2. In four cases (BRCA1, c.81-6T4A and c.498615G4T; BRCA2, c.76171 2T4G and c.875415G4A) a deleterious effect on RNA splicing was seen, whereas the c.135-15_-12del variant in BRCA1 showed no effect on RNA splicing. In the case of the BRCA2 c.68-7T4A variant, RNA analysis was not sufficient to establish the clinical significance. Six SSPPs were used to predict whether an effect on RNA splicing was expected for these six variants as well as for 23 intronic variants in BRCA1 for which the effect on RNA splicing has been published. Out of a total of 174 predictions, 161 (93%) were informative (i.e., the wild-type splice-site was recognized). No falsenegative predictions were observed; an effect on RNA splicing was always predicted by these programs. In four cases (2.5%) a false-positive prediction was observed. For DNA diagnostic laboratories, these programs are therefore very useful to select intronic variants that are likely to affect RNA splicing for further analysis.
Two mutations of the ATM gene were recently suggested to confer breast cancer risks similar to mutations of BRCA1 or BRCA2. Here, we set out to confirm these findings in 961 families with non-BRCA1/BRCA2 breast cancer from diverse geographical regions. We did not detect the ATM 7271T3 G mutation in any family. The ATM IVS10 -6T3 G mutation was detected in eight families, which was similar to its frequency among population-matched control individuals (pooled Mantel-Haenszel odds ratio ؍ 1.60; 95% confidence interval ؍ 0.48 to 5.35; P ؍ 0.44). Bayesian analysis of linkage in the ATM IVS10 -6T3 G-positive families showed an overall posterior probability of causality for this mutation of 0.008. We conclude that the ATM IVS10 -6T3 G mutation does not confer a significantly elevated breast cancer risk and that ATM 7271T3 G is a rare event in familial breast cancer.
Purpose: Since the identification of BRCA1 and BRCA2 , there has been no major breast cancer susceptibility gene discovered by linkage analysis in breast cancer families. This has been attributed to the heterogeneous genetic basis for the families under study. Recent studies have indicated that breast tumors arising in women carrying a BRCA1mutation have distinct histopathologic, immunophenotypic, and genetic features.To a lesser extent, this is also true for breast tumors from BRCA2 carriers.This indicates that it might be possible to decrease the geneticheterogeneity among families in which BRCA1 and BRCA2 have been excluded with high certainty (BRCAx families) if distinct subgroups of BRCAx-related breast tumors could be identified. Experimental Design: Loss of heterozygosity (LOH) analysis with at least one marker per chromosomal arm (65 markers) was used to characterize 100 breast tumors derived from 92 patients from 42 selected BRCAx families. In addition, the immunophenotype of 10 markers was compared with that of 31 BRCA1-and 21 BRCA2-related breast tumors. Results and Conclusions:The BRCAx-related tumors were characterized by more frequent LOH at 22q relative to sporadic breast cancer (P < 0.02), and differed significantly from BRCA1-and BRCA2-related tumors in their positivity for Bcl2. However, cluster analyses of the combined data (LOH and immunohistochemistry) did not result in subgroups that would allow meaningful subclassification of the families. On chromosomes 2, 3, 6, 12, 13, 21, and 22, we found markers at which LOH occurred significantly more frequent among the tumors from patients belonging to a single family than expected on the basis of overall LOH frequencies. Nonetheless, linkage analysis with markers for the corresponding regions on chromosomes 12, 21, and 22 did not reveal significant logarithm of the odds.A positive family history remains one of the most important risk factors for breast cancer, with first-degree relatives of patients having an approximately 2-fold elevated risk. About 15% of all patients have a first-degree relative with breast cancer, and although germ line mutations in BRCA1 and BRCA2 account for a substantial proportion of these cases (1), these mutations explain only 20% to 25% of the overall excess familial risk (2, 3). Mutations in other genes such as TP53 and PTEN are involved in rare multi-cancer syndromes and contribute very little to this risk. Mutations in BRCA1 and BRCA2 are strongly associated with families with at least four cases of breast cancer diagnosed before the age of 60 and one or more cases of ovarian cancer or male breast cancer (1). However, in families with four or five cases of breast cancer, and no ovarian or male breast cancer cases, BRCA1 and BRCA2 mutations were significantly less frequent. Because such a familial clustering is unlikely to have occurred by chance, this has been taken as evidence that other breast cancer susceptibility genes must exist (4).After the identification of BRCA1 and BRCA2, several chromosomal regions ...
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