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Derivation of Thymic Lymphoma T-cell Lines from Atm-/- and p53-/- Mice
Published on: April 3, 2011
ASXL1 and DNMT3A mutation in a cytogenetically normal B3 thymoma
R Belani1, G Oliveira2, G A Erikson2
1Medical Oncology Associates of San Diego, San Diego, CA, USA.
Abstract:
The molecular drivers of thymoma are poorly understood. Outside of the identification of rarely occurring epidermal growth factor receptor and v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog mutations via candidate gene sequencing, mutations in common cancer genes have yet to be observed. Only a single thymoma genome sequence has been previously reported, with no mutations in known cancer genes identified. Thus, we attempted to identify somatic driver mutations in a cytogenetically normal thymoma. A stage IVB type B3 thymoma from a 47-year-old male of Asian descent with no history of myasthenia gravis or other autoimmune condition was genomically evaluated. Exome sequencing and low-pass whole-genome sequencing was performed to identify somatic point mutations, copy number changes and structural variants. Mutations in known tumor suppressors DNMT3A (p.G728D) and ASXL1 (p.E657fs), consistent with mutations of known consequence in acute myeloid leukemia, were identified. Contrary to a previous report, this finding suggests the genetic etiology of thymomas may not be fundamentally distinct from other tumor types. Rather, these findings suggest that further sequencing of cytogenetically normal thymoma samples should reveal the specific molecular drivers of thymoma.
Insights
Molecular drivers of thymoma, a rare cancer, were investigated. Mutations in tumor suppressors DNMT3A and ASXL1 were identified, suggesting thymoma shares genetic causes with other cancers.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- The molecular underpinnings of thymoma remain largely unknown.
- Previous studies identified rare mutations in EGFR and KIT, but common cancer gene mutations were absent.
- Only one prior whole-genome sequence of thymoma has been reported, revealing no known cancer gene mutations.
Purpose of the Study:
- To identify somatic driver mutations in cytogenetically normal thymoma.
- To investigate the genomic landscape of thymoma to understand its genetic etiology.
Main Methods:
- Whole-exome sequencing and low-pass whole-genome sequencing were employed.
- Genomic evaluation of a stage IVB type B3 thymoma sample from a 47-year-old male.
- Analysis focused on identifying somatic point mutations, copy number alterations, and structural variants.
Main Results:
- Mutations in known tumor suppressors DNMT3A (p.G728D) and ASXL1 (p.E657fs) were identified.
- These mutations are consistent with those observed in acute myeloid leukemia.
- The findings challenge the notion that thymoma's genetic basis is distinct from other malignancies.
Conclusions:
- Thymoma may share common molecular drivers with other cancer types.
- Further genomic sequencing of cytogenetically normal thymomas is warranted to uncover specific drivers.
- This study provides new insights into the genetic landscape of thymoma.
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