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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

(a) Thymoma imaging. fluorodeoxyglucose positron emission tomography/computed tomography (CT) demonstrates intensely hypermetabolic anterior mediastinal mass on fused coronal and axial images (arrowheads). Cystic tumor component on attenuation-correction CT image is non-hypermetabolic on FDG PET (arrows). (b) Renal tumor imaging. CT scan with contrast (left) demonstrates large contrast-enhancing left renal mass (arrowheads) with posterior hydronephrotic upper pole collecting system (block arrow). Fused axial FDG PET/CT (right) demonstrates mildly hypermetabolic posterior tumor component (arrow). Upper pole hydronephrosis contains excreted urinary FDG (block arrow). (c, d) Thymoma histology. (c) Lobules of thymoma tumor cells infiltrate into the adjacent lung parenchyma (arrows: hematoxylin and eosin (H&E): × 5 magnification). (d) Sheets of thymoma type B3 polygonal tumor cells with ovoid nuclei (H&E: × 20 magnification). (e) Tumor genome overview. Circos plot overview of somatic mutations identified in the thymoma. Outer text denotes location and gene impacted by somatic protein coding mutations. Middle gray ring depicts copy number variation (CNV) status (black=2 copies, red=CNV gains, blue=CNV losses). Inner text displays genes overlapping identified CNVs. Inner red lines display identified structural variants.
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fig1: (a) Thymoma imaging. fluorodeoxyglucose positron emission tomography/computed tomography (CT) demonstrates intensely hypermetabolic anterior mediastinal mass on fused coronal and axial images (arrowheads). Cystic tumor component on attenuation-correction CT image is non-hypermetabolic on FDG PET (arrows). (b) Renal tumor imaging. CT scan with contrast (left) demonstrates large contrast-enhancing left renal mass (arrowheads) with posterior hydronephrotic upper pole collecting system (block arrow). Fused axial FDG PET/CT (right) demonstrates mildly hypermetabolic posterior tumor component (arrow). Upper pole hydronephrosis contains excreted urinary FDG (block arrow). (c, d) Thymoma histology. (c) Lobules of thymoma tumor cells infiltrate into the adjacent lung parenchyma (arrows: hematoxylin and eosin (H&E): × 5 magnification). (d) Sheets of thymoma type B3 polygonal tumor cells with ovoid nuclei (H&E: × 20 magnification). (e) Tumor genome overview. Circos plot overview of somatic mutations identified in the thymoma. Outer text denotes location and gene impacted by somatic protein coding mutations. Middle gray ring depicts copy number variation (CNV) status (black=2 copies, red=CNV gains, blue=CNV losses). Inner text displays genes overlapping identified CNVs. Inner red lines display identified structural variants.

Mentions: The patient presented with a 3-month history of cough. He did not have shortness of breath, hemoptysis or weight loss at presentation. He also did not have neurologic symptoms consistent with myasthenia gravis. Family history is significant for thymoma in the mother. A computed tomography of the chest showed a mediastinal mass measuring 10.5 × 7.8 × 12.1 cm and a large (12 × 9.5 × 8.3 cm) left renal mass (Figures 1a and 1b, ). The patient underwent computed tomography-guided biopsy of the mediastinal mass that revealed mildly atypical, uniform spindled cells associated with dense collagenous tissue. The tumor cells showed immunohistochemical positivity for AE1/AE3 and cytokeratin-7. Immunohistochemical markers for renal cell carcinoma were negative. The pathologic findings were consistent with thymoma. Subsequently, the patient underwent removal of mediastinal mass and right upper lobectomy as an en bloc resection. There was a separate right diaphragmatic nodule that was also excised. At the time of surgery, it was noted that the tumor was densely adherent to the pericardium and invaded the upper lobe of the right lung. Microscopic examination showed spindled to polygonal cells in varying sized lobules with accompanying fibrous bands of stroma invading the pericardium, pleura and lung (Figures 1c and d). Only occasional interspersed lymphocytes were seen. Focal lymph-vascular invasion was identified. The tumor cells showed ovoid nuclei with mild pleomorphism and scattered mitoses. The final margins were clear. The diaphragmatic nodule demonstrated tumor cells morphologically similar to the primary tumor. The final Masaoka stage of IVB was based on the finding of a separate distinct diaphragmatic tumor nodule and pleural invasion. The tumor had a WHO histologic category of B3 based on the predominance of epithelial cells and paucity of intraepithelial lymphocytes. No treatment was given before genome sequencing.


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)

(a) Thymoma imaging. fluorodeoxyglucose positron emission tomography/computed tomography (CT) demonstrates intensely hypermetabolic anterior mediastinal mass on fused coronal and axial images (arrowheads). Cystic tumor component on attenuation-correction CT image is non-hypermetabolic on FDG PET (arrows). (b) Renal tumor imaging. CT scan with contrast (left) demonstrates large contrast-enhancing left renal mass (arrowheads) with posterior hydronephrotic upper pole collecting system (block arrow). Fused axial FDG PET/CT (right) demonstrates mildly hypermetabolic posterior tumor component (arrow). Upper pole hydronephrosis contains excreted urinary FDG (block arrow). (c, d) Thymoma histology. (c) Lobules of thymoma tumor cells infiltrate into the adjacent lung parenchyma (arrows: hematoxylin and eosin (H&E): × 5 magnification). (d) Sheets of thymoma type B3 polygonal tumor cells with ovoid nuclei (H&E: × 20 magnification). (e) Tumor genome overview. Circos plot overview of somatic mutations identified in the thymoma. Outer text denotes location and gene impacted by somatic protein coding mutations. Middle gray ring depicts copy number variation (CNV) status (black=2 copies, red=CNV gains, blue=CNV losses). Inner text displays genes overlapping identified CNVs. Inner red lines display identified structural variants.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig1: (a) Thymoma imaging. fluorodeoxyglucose positron emission tomography/computed tomography (CT) demonstrates intensely hypermetabolic anterior mediastinal mass on fused coronal and axial images (arrowheads). Cystic tumor component on attenuation-correction CT image is non-hypermetabolic on FDG PET (arrows). (b) Renal tumor imaging. CT scan with contrast (left) demonstrates large contrast-enhancing left renal mass (arrowheads) with posterior hydronephrotic upper pole collecting system (block arrow). Fused axial FDG PET/CT (right) demonstrates mildly hypermetabolic posterior tumor component (arrow). Upper pole hydronephrosis contains excreted urinary FDG (block arrow). (c, d) Thymoma histology. (c) Lobules of thymoma tumor cells infiltrate into the adjacent lung parenchyma (arrows: hematoxylin and eosin (H&E): × 5 magnification). (d) Sheets of thymoma type B3 polygonal tumor cells with ovoid nuclei (H&E: × 20 magnification). (e) Tumor genome overview. Circos plot overview of somatic mutations identified in the thymoma. Outer text denotes location and gene impacted by somatic protein coding mutations. Middle gray ring depicts copy number variation (CNV) status (black=2 copies, red=CNV gains, blue=CNV losses). Inner text displays genes overlapping identified CNVs. Inner red lines display identified structural variants.
Mentions: The patient presented with a 3-month history of cough. He did not have shortness of breath, hemoptysis or weight loss at presentation. He also did not have neurologic symptoms consistent with myasthenia gravis. Family history is significant for thymoma in the mother. A computed tomography of the chest showed a mediastinal mass measuring 10.5 × 7.8 × 12.1 cm and a large (12 × 9.5 × 8.3 cm) left renal mass (Figures 1a and 1b, ). The patient underwent computed tomography-guided biopsy of the mediastinal mass that revealed mildly atypical, uniform spindled cells associated with dense collagenous tissue. The tumor cells showed immunohistochemical positivity for AE1/AE3 and cytokeratin-7. Immunohistochemical markers for renal cell carcinoma were negative. The pathologic findings were consistent with thymoma. Subsequently, the patient underwent removal of mediastinal mass and right upper lobectomy as an en bloc resection. There was a separate right diaphragmatic nodule that was also excised. At the time of surgery, it was noted that the tumor was densely adherent to the pericardium and invaded the upper lobe of the right lung. Microscopic examination showed spindled to polygonal cells in varying sized lobules with accompanying fibrous bands of stroma invading the pericardium, pleura and lung (Figures 1c and d). Only occasional interspersed lymphocytes were seen. Focal lymph-vascular invasion was identified. The tumor cells showed ovoid nuclei with mild pleomorphism and scattered mitoses. The final margins were clear. The diaphragmatic nodule demonstrated tumor cells morphologically similar to the primary tumor. The final Masaoka stage of IVB was based on the finding of a separate distinct diaphragmatic tumor nodule and pleural invasion. The tumor had a WHO histologic category of B3 based on the predominance of epithelial cells and paucity of intraepithelial lymphocytes. No treatment was given before genome sequencing.

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