Analysis of BRCA1 genomic structure: novel germline mutations and somatic alterations in breast cancer
Payne, Shannon Renée, 1970-
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Germline mutations in BRCA1 lead to an increased risk of breast and ovarian cancer, with loss of the second, normal allele critical to tumorigenesis. The relative lack of somatic mutations in BRCA1 , however, has argued against its involvement in non-inherited (sporadic) breast cancer. One explanation for this contradiction is that BRCA1 mutations exist in sporadic breast carcinomas, but are not identified by current mutation screening procedures. My research specifically addressed the types and frequencies of large genomic rearrangements responsible for inactivation of BRCA1. I characterized the types of large rearrangements that occur within the BRCA1 region and investigated the contribution of two large germline rearrangements to breast cancer in a population-based series of breast cancer patients. Although the structure of the BRCA1 genomic region was generally well-conserved, one variant allele containing multiple large alterations of the BRCA1 genomic region was identified. The existence of a variant with multiple large rearrangements in cis indicates that an investigation of the types and frequencies of noncoding variation in the BRCA1 genomic region may yield a broader understanding of noncoding variation within the human genome.One argument for the role of BRCA1 in sporadic breast cancer has been the high rate of allelic loss observed for the BRCA1 locus. In order to determine whether BRCA1 is inactivated somatically by large rearrangements of BRCA1, I analyzed 92 breast carcinomas for genomic loss in the BRCA1 region of chromosome 17q. I investigated genomic loss using a combination of loss of heterozygosity (LOH), Long PCR, and Southern analysis. Although two large germline rearrangements were detected in our series, no large somatic rearrangements were identified. LOH results were correlated with BRCA1 protein immunohistochemistry data generated by Rachel Gonzalez-Hernandez in order to test whether LOH is a mechanism for inactivating BRCA1 in sporadic breast cancer. Reduced BRCA1 protein in sporadic breast carcinomas was associated significantly with loss of the most 5' BRCA1 intragenic marker, D17S1323. LOH at the more 3' BRCA1 intragenic markers was not associated with reduced BRCA1 protein. Interestingly, 8 of 14 breast carcinomas retaining all three BRCA1 intragenic markers showed reduced BRCA1 protein. Thus, there are likely other mechanisms for inactivation of BRCA1 in sporadic breast cancer.
- Genetics