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Low incidence of BRCA2 mutations in breast carcinoma and other cancers
D H Teng1, R Bogden, J Mitchell
1Myriad Genetics, Inc., Salt Lake City, Utah 84108, USA.
Abstract:
Inherited mutant alleles of familial tumour suppressor genes predispose individuals to particular types of cancer. In addition to an involvement in inherited susceptibility to cancer, these tumour suppressor genes are targets for somatic mutations in sporadic cancers of the same type found in the familial forms. An exception is BRCA1, which contributes to a significant fraction of familial breast and ovarian cancer, but undergoes mutation at very low rates in sporadic breast and ovarian cancers. This finding suggests that other genes may be the principal targets for somatic mutation in breast carcinoma. A second, recently identified familial breast cancer gene, BRCA2 (refs 5-8), accounts for a proportion of breast cancer roughly equal to BRCA1. Like BRCA1, BRCA2 behaves as a dominantly inherited tumour suppressor gene. Individuals who inherit one mutant allele are at increased risk for breast cancer, and the tumours they develop lose the wild-type allele by heterozygous deletion. The BRCA2 coding sequence is huge, composed of 26 exons that span 10,443 bp. Here we investigate the rate of BRCA2 mutation in sporadic breast cancers and in a set of cell lines that represent twelve other tumour types. Surprisingly, mutations in BRCA2 are infrequent in cancers including breast carcinoma. However, a probable germline mutation in a pancreatic tumour cell line suggests a role for BRCA2 in susceptibility to pancreatic cancer.
Insights
Mutations in the BRCA2 gene are rare in sporadic breast cancers, suggesting other genes are more commonly involved. However, a potential BRCA2 mutation in pancreatic cancer cell lines indicates its possible role in pancreatic cancer susceptibility.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Familial tumor suppressor genes predispose individuals to specific cancers.
- BRCA1 is linked to familial breast and ovarian cancer but rarely mutated in sporadic forms.
- BRCA2 is a recently identified familial breast cancer gene, similar to BRCA1 in inheritance and risk.
Purpose of the Study:
- To investigate the mutation rate of the BRCA2 gene in sporadic breast cancers.
- To examine BRCA2 mutations in cell lines from twelve other tumor types.
- To assess the role of BRCA2 in sporadic cancer development.
Main Methods:
- Analysis of BRCA2 gene mutations in sporadic breast cancer samples.
- Screening of BRCA2 in cell lines representing diverse tumor types.
- Investigation of germline mutations in tumor cell lines.
Main Results:
- BRCA2 mutations were found to be infrequent in sporadic breast carcinoma.
- Mutations in BRCA2 were also rare across cell lines from twelve other tumor types.
- A probable germline mutation in a pancreatic tumor cell line suggests a potential role for BRCA2 in pancreatic cancer.
Conclusions:
- BRCA2 mutations are not a primary driver in most sporadic breast cancers.
- The findings suggest other genes are more frequently targeted by somatic mutations in sporadic breast cancer.
- BRCA2 may play a role in the susceptibility to pancreatic cancer.