Genetic profile of thymic epithelial tumors in the Japanese population: an exploratory study examining potential therapeutic targets

Midori Shimada; Hirokazu Taniguchi; Hiroyuki Yamaguchi; Hiroshi Gyotoku; Daisuke Sasaki; Norihito Kaku; Chikako Senju; Hiroaki Senju; Erika Imamura; Shinnosuke Takemoto; Kazuko Yamamoto; Noriho Sakamoto; Yasushi Obase; Tomoshi Tsuchiya; Minoru Fukuda; Hiroshi Soda; Kazuto Ashizawa; Junya Fukuoka; Takeshi Nagayasu; Katsunori Yanagihara; Hiroshi Mukae

doi:10.21037/tlcr-22-794

Genetic profile of thymic epithelial tumors in the Japanese population: an exploratory study examining potential therapeutic targets

Transl Lung Cancer Res. 2023 Apr 28;12(4):707-718. doi: 10.21037/tlcr-22-794. Epub 2023 Mar 23.

Authors

Midori Shimada^{1

2}, Hirokazu Taniguchi¹, Hiroyuki Yamaguchi^{1

3}, Hiroshi Gyotoku¹, Daisuke Sasaki⁴, Norihito Kaku^{4

5}, Chikako Senju^{6

7}, Hiroaki Senju^{1

7}, Erika Imamura¹, Shinnosuke Takemoto¹, Kazuko Yamamoto^{1

8}, Noriho Sakamoto¹, Yasushi Obase¹, Tomoshi Tsuchiya^{9

10}, Minoru Fukuda^{3

11}, Hiroshi Soda¹², Kazuto Ashizawa³, Junya Fukuoka¹³, Takeshi Nagayasu⁹, Katsunori Yanagihara⁴, Hiroshi Mukae¹

Affiliations

¹ Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
² Clinical Research Center, Nagasaki University Hospital, Nagasaki, Japan.
³ Clinical Oncology Center, Nagasaki University Hospital, Nagasaki, Japan.
⁴ Department of Laboratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
⁵ Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
⁶ Department of Plastic and Reconstructive Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
⁷ Senju Hospital, Sasebo, Japan.
⁸ Division of Infectious, Respiratory, and Digestive Medicine, First Department of Internal Medicine, University of the Ryukyus Graduate School of Medicine, Okinawa, Japan.
⁹ Department of Surgical Oncology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
¹⁰ Department of Thoracic Surgery, Faculty of Medicine, Academic Assembly, University of Toyama, Toyama, Japan.
¹¹ Department of Respiratory Medicine, Nagasaki Prefecture Shimabara Hospital, Shimabara, Japan.
¹² Department of Respiratory Medicine, Sasebo City General Hospital, Sasebo, Japan.
¹³ Department of Pathology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.

Abstract

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.

Keywords: Thymic epithelial tumors; genetic profile; next generation sequencing.