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Updated: Aug 18, 2026
Identifying the Effects of BRCA1 Mutations on Homologous Recombination using Cells that Express Endogenous Wild-type BRCA1
Published on: February 17, 2011
A somatic BRCA2 mutation in RER+ endometrial carcinomas that specifically deletes the amino-terminal transactivation
1Department of Oncology, University Hospital, Lund, Sweden. anjila.koul@onk.lu.se
Abstract:
Mismatch repair deficiency and replication errors (RERs) occur in approximately 20% of sporadic endometrial carcinomas. Frameshift mutations in several cancer predisposing genes, especially in their mononucleotide repeats, are seen in RER+ tumors. In a survey of hereditary breast cancer genes in gynecological cancer, we analyzed the entire coding sequence of BRCA1 and BRCA2 in 51 endometrial tumors, of which 12 were RER+. Seven somatic mutations were identified in six (50%) of the RER+ tumors, but none in RER- tumors. A novel base pair deletion at a (T)10 tract in BRCA2 intron 2, causing an in-frame splice deletion of exon 3, was observed in four tumors, one of which contained a second, truncating BRCA2 mutation. Two tumors exhibited frameshift mutations at polyA tracts in BRCA1 and BRCA2 exon 11, both predicted to result in premature translation termination. Whereas most mutations in BRCA1 and BRCA2 are known to affect the more carboxy-terminal regions interacting with RAD51, and the transactivating BRCT domains of BRCA1, this is the first demonstration of a recurrent BRCA2 mutation that specifically deletes the amino-terminal transactivation domain. Moreover, our results suggest that somatic mutations in BRCA2(and to some extent BRCA1) may confer a growth advantage in RER+ endometrial carcinomas.
Insights
Somatic mutations in BRCA1 and BRCA2 genes were found in 50% of replication error-positive endometrial tumors. These findings suggest these mutations may drive tumor growth in RER+ endometrial carcinomas.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Mismatch repair deficiency and replication errors (RERs) are present in about 20% of sporadic endometrial carcinomas.
- Frameshift mutations in cancer predisposing genes are common in RER+ tumors, particularly within mononucleotide repeats.
Purpose of the Study:
- To investigate the frequency and types of somatic mutations in BRCA1 and BRCA2 genes in endometrial tumors.
- To determine if mutations in these hereditary breast cancer genes are associated with replication error-positive (RER+) status in endometrial cancer.
Main Methods:
- Analysis of the entire coding sequence of BRCA1 and BRCA2 genes in 51 endometrial tumors.
- Classification of tumors into RER-positive (RER+) and RER-negative (RER-) groups.
- Identification and characterization of somatic mutations within the analyzed genes.
Main Results:
- Seven somatic mutations were identified in six (50%) of the 12 RER+ endometrial tumors.
- No mutations were found in RER- tumors.
- A recurrent BRCA2 mutation involving deletion of exon 3 was observed in four tumors.
- Frameshift mutations in BRCA1 and BRCA2 exon 11 were found in two tumors, leading to premature translation termination.
- The identified BRCA2 mutation specifically deletes the amino-terminal transactivation domain.
Conclusions:
- Somatic mutations in BRCA1 and BRCA2 occur in a significant proportion of RER+ endometrial carcinomas.
- The recurrent BRCA2 mutation affecting the amino-terminal transactivation domain is a key finding.
- These somatic mutations may confer a growth advantage in RER+ endometrial carcinomas, highlighting their potential role in tumorigenesis.
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