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ASXL1 and DNMT3A mutation in a cytogenetically normal B3 thymoma.

Belani R, Oliveira G, Erikson GA, Ra S, Schechter MS, Lee JK, Shipman WJ, Haaser SM, Torkamani A - Oncogenesis (2014)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Medical 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.

No MeSH data available.


Related in: MedlinePlus

The ASXL1 p.E657fs mutation observed in this thymoma sample is visualized in the context of other ASXL1 mutations observed in all tumor genome sequences catalogued in TCGA. The protein sequence and functional domains are depicted on the x axis. The number of TCGA mutations is depicted on the y axis. Red circles correspond to truncating mutations. Green circles correspond to nonsynonymous mutations. Purple circles correspond to mutations that are both nonsynonymous and truncating in different gene isoforms. Circle height corresponds to the number of mutations per position, however, the E657fs indicator (black) is only meant to indicate position of this mutation. Note the clustering of TCGA truncating mutations around position 657. The Sanger sequencing validation trace of p.E657fs is also shown, demonstrating validation of p.E657fs as a heterozygous somatic mutation.
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fig3: The ASXL1 p.E657fs mutation observed in this thymoma sample is visualized in the context of other ASXL1 mutations observed in all tumor genome sequences catalogued in TCGA. The protein sequence and functional domains are depicted on the x axis. The number of TCGA mutations is depicted on the y axis. Red circles correspond to truncating mutations. Green circles correspond to nonsynonymous mutations. Purple circles correspond to mutations that are both nonsynonymous and truncating in different gene isoforms. Circle height corresponds to the number of mutations per position, however, the E657fs indicator (black) is only meant to indicate position of this mutation. Note the clustering of TCGA truncating mutations around position 657. The Sanger sequencing validation trace of p.E657fs is also shown, demonstrating validation of p.E657fs as a heterozygous somatic mutation.

Mentions: ASXL1 is a chromatin binding Polycomb group protein involved in transcriptional repression of numerous cell-type-specific systems, most likely through the recruitment of methylated histone H3 to promoters of target genes.24ASXL1 is a known tumor suppressor in myelodysplastic syndrome and chronic myelomonocytic leukemia although it is frequently mutated in other tumor types such as lung squamous and bladder cancer.17, 18 The heterozygous deletion of a single guanine nucleotide within exon 12 of ASXL1 leads to out-of-frame translation beginning at codon 657 and premature truncation of the protein, removing >50% of the protein including the PHD domain responsible from histone interactions. This mutation was confirmed via Sanger sequencing (Figure 3, inset). Similar heterozygous C-terminal truncations are sufficient to induce myelodysplastic syndrome.25 Previously observed frameshift or nonsense mutations in ASXL1 across numerous tumor types catalogued in The Cancer Genome Atlas (TCGA) have been observed both upstream and downstream of amino-acid 657, with the highest concentration centered at position 657 (Figure 3). In fact, the majority of previously observed ASXL1 mutations occur in the same exon as this mutation, exon 12.26, 27 Thus, both the type and location of this somatic mutation strongly suggests mutations in ASXL1 have a causal role in the etiology of thymomas.


ASXL1 and DNMT3A mutation in a cytogenetically normal B3 thymoma.

Belani R, Oliveira G, Erikson GA, Ra S, Schechter MS, Lee JK, Shipman WJ, Haaser SM, Torkamani A - Oncogenesis (2014)

The ASXL1 p.E657fs mutation observed in this thymoma sample is visualized in the context of other ASXL1 mutations observed in all tumor genome sequences catalogued in TCGA. The protein sequence and functional domains are depicted on the x axis. The number of TCGA mutations is depicted on the y axis. Red circles correspond to truncating mutations. Green circles correspond to nonsynonymous mutations. Purple circles correspond to mutations that are both nonsynonymous and truncating in different gene isoforms. Circle height corresponds to the number of mutations per position, however, the E657fs indicator (black) is only meant to indicate position of this mutation. Note the clustering of TCGA truncating mutations around position 657. The Sanger sequencing validation trace of p.E657fs is also shown, demonstrating validation of p.E657fs as a heterozygous somatic mutation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4150211&req=5

fig3: The ASXL1 p.E657fs mutation observed in this thymoma sample is visualized in the context of other ASXL1 mutations observed in all tumor genome sequences catalogued in TCGA. The protein sequence and functional domains are depicted on the x axis. The number of TCGA mutations is depicted on the y axis. Red circles correspond to truncating mutations. Green circles correspond to nonsynonymous mutations. Purple circles correspond to mutations that are both nonsynonymous and truncating in different gene isoforms. Circle height corresponds to the number of mutations per position, however, the E657fs indicator (black) is only meant to indicate position of this mutation. Note the clustering of TCGA truncating mutations around position 657. The Sanger sequencing validation trace of p.E657fs is also shown, demonstrating validation of p.E657fs as a heterozygous somatic mutation.
Mentions: ASXL1 is a chromatin binding Polycomb group protein involved in transcriptional repression of numerous cell-type-specific systems, most likely through the recruitment of methylated histone H3 to promoters of target genes.24ASXL1 is a known tumor suppressor in myelodysplastic syndrome and chronic myelomonocytic leukemia although it is frequently mutated in other tumor types such as lung squamous and bladder cancer.17, 18 The heterozygous deletion of a single guanine nucleotide within exon 12 of ASXL1 leads to out-of-frame translation beginning at codon 657 and premature truncation of the protein, removing >50% of the protein including the PHD domain responsible from histone interactions. This mutation was confirmed via Sanger sequencing (Figure 3, inset). Similar heterozygous C-terminal truncations are sufficient to induce myelodysplastic syndrome.25 Previously observed frameshift or nonsense mutations in ASXL1 across numerous tumor types catalogued in The Cancer Genome Atlas (TCGA) have been observed both upstream and downstream of amino-acid 657, with the highest concentration centered at position 657 (Figure 3). In fact, the majority of previously observed ASXL1 mutations occur in the same exon as this mutation, exon 12.26, 27 Thus, both the type and location of this somatic mutation strongly suggests mutations in ASXL1 have a causal role in the etiology of thymomas.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Medical 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.

No MeSH data available.


Related in: MedlinePlus