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Genetic profile of thymic epithelial tumors in the Japanese population: an exploratory study examining potential
Midori Shimada1,2, Hirokazu Taniguchi1, Hiroyuki Yamaguchi1,3
1Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Background:
Thymic epithelial tumors (TETs) are prone to developing in East Asian populations. However, little is known about the genomic profile of TETs in East Asian populations, and the genomic aberrations in TETs have not yet been fully clarified. Thus, molecular targeted therapies for patients with TETs have not been established. This prospective study was conducted to explore the genetic abnormalities of surgically resected TETs in a Japanese cohort and to identify clues for carcinogenesis and potential therapeutic targets in TETs.
Methods:
Genetic profiles of TETs were investigated using fresh-frozen specimens resected from operable cases with TETs. DNA sequencing was performed using a next-generation sequencing (NGS) gene panel test with Ion Reporter™ and CLC Genomics Workbench 11.0. The mutation sites were further confirmed by Sanger sequencing, digital droplet polymerase chain reaction (ddPCR), and TA cloning for validation.
Results:
Among 43 patients diagnosed with anterior mediastinal tumors between January 2013 and March 2019, NGS and validation analyses were performed in 31 patients [29 thymomas and two thymic cancers (TCs)] who met the study criteria. Of these, 12 cases of thymoma types A, AB, B1, and B2 harbored the general transcription factor 2-I (GTF2I) mutation (L424H). Conversely, the mutation was not detected in type B3 thymoma or TC, suggesting that the GTF2I mutation existed in indolent types of TETs. Rat sarcoma viral oncogene (RAS) mutations were detected in three cases [Harvey RAS (HRAS) in two cases of type AB thymoma and neuroblastoma RAS (NRAS)] in one case of type B1 thymoma), and additional sex combs like 1 (ASXL1) mutation was present in one case of TC. All RAS mutations were observed in GTF2I-mutated cases.
Conclusions:
The GTF2I mutation (L424H) is the most frequently occurring mutation in the limited histology of thymoma, consistent with those in the non-Asian population. HRAS and NRAS mutations co-occurred in cases harboring the GTF2I mutation. These findings suggest that the existence of the GTF2I mutation might be related to indolent types of TETs, and RAS mutations could be candidates as therapeutic targets in TETs.
Insights
The general transcription factor 2-I (GTF2I) mutation is common in indolent thymic epithelial tumors (TETs). RAS mutations co-occurred with GTF2I mutations, suggesting potential therapeutic targets for TETs.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Thymic epithelial tumors (TETs) are more prevalent in East Asian populations.
- The genomic profile of TETs in East Asian populations remains largely unknown.
- Lack of established molecular targeted therapies for TETs necessitates further research.
Purpose of the Study:
- To investigate genetic abnormalities in surgically resected TETs from a Japanese cohort.
- To identify potential carcinogenic clues and therapeutic targets for TETs.
- To elucidate the genomic landscape of TETs in an East Asian population.
Main Methods:
- Next-generation sequencing (NGS) gene panel test was employed on fresh-frozen TET specimens.
- Mutation sites were validated using Sanger sequencing, digital droplet polymerase chain reaction (ddPCR), and TA cloning.
- Analysis included 31 patients with thymomas and thymic cancers (TCs).
Main Results:
- The general transcription factor 2-I (GTF2I) mutation (L424H) was identified in 12 cases of indolent thymoma types (A, AB, B1, B2).
- GTF2I mutations were absent in type B3 thymoma and TC.
- Rat sarcoma viral oncogene (RAS) mutations (HRAS, NRAS) were found in three GTF2I-mutated cases; an ASXL1 mutation was observed in one TC.
Conclusions:
- The GTF2I mutation (L424H) is a frequent finding in specific thymoma subtypes, aligning with findings in non-Asian populations.
- Co-occurrence of RAS mutations with GTF2I mutations suggests a potential role in TET development.
- GTF2I mutations may indicate indolent TET types, and RAS mutations represent potential therapeutic targets.
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