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Published on: August 12, 2015
Mutational analyses of RB and BRCA2 as candidate tumour suppressor genes in parathyroid carcinoma
Trisha M Shattuck1, Teresa S Kim, Jessica Costa
1Center for Molecular Medicine and Division of Endocrinology & Metabolism, University of Connecticut School of Medicine, Farmington, 06030-3101, USA.
Objective:
Strong evidence indicates that at least one key tumour suppressor gene important for the development of malignant parathyroid tumours is located on chromosome 13, but the critical target gene remains unknown. Importantly, the region of acquired DNA loss includes two established tumour suppressor genes, the retinoblastoma gene, RB (RB1) and BRCA2. Resolution of whether RB or BRCA2 is the critical 13q tumour suppressor gene in parathyroid cancer requires analysis of these genes' sequences for intragenic inactivating mutations. Therefore, RB and BRCA2 were analysed in a group of parathyroid carcinomas in which mutations of these genes should be most readily detectable.
Patients And Design:
Six parathyroid carcinomas from four patients which showed loss of heterozygosity (LOH) at the RB locus and/or 13q loss by comparative genomic hybridazation (CGH) were selected from a CGH/LOH-screened panel of 16 carcinoma specimens from 10 patients. These tumours were examined for mutations by direct sequencing of the complete 27-exon coding region, intron-exon boundaries and promoter of RB. The 26 coding exons and intron-exon boundaries of BRCA2 were also directly sequenced in seven parathyroid carcinomas with loss in the BRCA2 region.
Results:
No microdeletions, insertions, or point mutations were detected in either RB or BRCA2 in any of the carcinomas.
Conclusion:
The absence of tumour-specific somatic mutations in RB and BRCA2 suggests that they are unlikely to act as classic tumour suppressor genes in the pathogenesis of parathyroid carcinomas. While decreased expression of these genes might contribute to parathyroid carcinomatosis in a secondary fashion and 13q loss warrants further study as a diagnostic marker for parathyroid carcinoma, the putative 13q tumour suppressor awaits identification.
Insights
Researchers investigated the retinoblastoma gene (RB) and BRCA2 in parathyroid carcinomas. No mutations were found, suggesting these genes are not primary drivers of parathyroid cancer development.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Malignant parathyroid tumors are associated with chromosome 13 alterations.
- The specific tumor suppressor gene responsible for parathyroid cancer on chromosome 13 remains unidentified.
- Both the retinoblastoma gene (RB) and BRCA2 are located in a region of DNA loss in parathyroid carcinomas.
Purpose of the Study:
- To determine if mutations in the RB or BRCA2 genes are responsible for parathyroid cancer.
- To analyze the sequences of RB and BRCA2 for inactivating mutations in parathyroid carcinomas.
Main Methods:
- Six parathyroid carcinomas with loss of heterozygosity (LOH) at the RB locus or 13q loss were selected.
- Direct sequencing was used to analyze the RB and BRCA2 genes, including coding regions, intron-exon boundaries, and promoter regions.
- Seven parathyroid carcinomas with BRCA2 region loss were analyzed for BRCA2 mutations.
Main Results:
- No intragenic inactivating mutations, including microdeletions, insertions, or point mutations, were detected in either the RB or BRCA2 genes in any of the analyzed parathyroid carcinomas.
- The study found no evidence of tumor-specific somatic mutations in RB or BRCA2.
Conclusions:
- The absence of mutations suggests RB and BRCA2 are unlikely to be classic tumor suppressor genes in parathyroid cancer pathogenesis.
- Further research is needed to identify the specific tumor suppressor gene on chromosome 13.
- Chromosome 13q loss may serve as a diagnostic marker for parathyroid carcinoma.
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