ASXL1 and DNMT3A mutation in a cytogenetically normal B3 thymoma

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.

Mutations of epigenetic regulatory genes are common in thymic carcinomas

“…All DNMT3A mutations occurred in the catalytic domain ( Figure 3A ), which may result in impairment of enzymatic activity 37 . Similar DNMT3A mutations with high frequency spreading around the catalytic domain were also found in T-cell lymphomas, acute myeloid leukemia and recently a B2 thymoma 30 34 38 .…”

“…Two ASXL1 nonsense mutations (C594* and Y700*) were identified in two TCs and one missense (D756A) in a B2 thymoma ( Figure 3A and Tables S2 ). A nonsense mutation of ASXL1 has been recently reported in a cytogenetically normal B3 thymoma 30 . Recurrent somatic ASXL1 mutations also occur in myelodysplastic syndrome, myeloproliferative neoplasms, and acute myeloid leukemia, and are associated with adverse outcome 31 .…”

Gene-Specific Methylation Analysis in Thymomas of Patients with Myasthenia Gravis

“…Studies performed in mice with conditional knockout of Dnmt3a revealed a role for DNA methylation in mediating the self-renewal and differentiation of normal hematopoietic stem cells and leukemia stem cells [33]. A functional role of this gene in thymic epithelial tumors emerged from studies that focused on mutation analysis, revealing that DNMT3A is one the most frequently mutated genes in thymic carcinoma [34], and that the mutation p.G728D is associated with B3 thymomas [35]. Similarly, a SNP in the promoter of DNMT3B , namely −579G>T, was associated with TAMG [36], overall suggesting a contribution of de novo DNMTs in thymomas.…”

PI3K as a Potential Therapeutic Target in Thymic Epithelial Tumors

“…6,16–23 Such genetic differences, combined with the histology-based classification system, are clinically relevant for both prognosis and treatment of TETs and may contribute to identification of new molecular targets for therapeutic intervention. 3,7,19,20 …”