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High Prevalence of DICER1 Mutations and Low Frequency of Gene Fusions in Pediatric Follicular-Patterned Tumors of the Thyroid

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Abstract

Follicular-patterned tumors of the thyroid in the adult population frequently harbor RAS mutations or PAX8-PPARG rearrangement, but little is known about molecular profiles in the pediatric patients with thyroid tumors, which is rare. To identify the molecular profile of pediatric follicular-patterned tumors, we enrolled 41 pediatric patients with follicular-patterned tumors from two institutions. We did next-generation sequencing using a mutation panel targeting 49 thyroid-tumor-related genes and a fusion panel targeting 88 types of thyroid-related gene fusions. We identified nonsynonymous mutations in at least one target gene in most of the tumors (28/41, 68%). Somatic DICER1 mutations (22%, n = 9) were the most common genetic alteration, followed by mutations of NRAS (15%), FGFR3 (15%), PTEN (12%), and STK11 (10%). Infrequent genetic alterations (≤ 5% of all cases) included mutations of HRAS, APC, TSHR, CTNNB1, TP53, EIF1AX, FGFR4, GNAS, RET, and SOS1, and gene fusion of THADA-IGF2BP3. DICER1 and RAS mutations were mutually exclusive. No patients had tumors related to the DICER1 syndrome or the Cowden syndrome. There was no significant difference in total mutation burden or distribution between follicular adenoma and follicular carcinoma. In the literature, the DICER1 mutation has been reported in 20 to 53% of pediatric patients with follicular-patterned tumors. In conclusion, our study reinforces the role of the DICER1 mutation in the development of pediatric thyroid tumors. Gene fusions rarely occur in pediatric follicular-patterned tumors. Mutation or gene fusion alone could not distinguish benign from malignant follicular-patterned tumors in pediatric patients.

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All data analyzed during this study are included in this published article and its supplementary information files.

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Funding

This research was supported by grants (NRF-2020-R1F1A1070028, NRF-2019-R1A5A2027588, NRF-2019-R1C1C1004909, and NRF-2017-R1E1A1A01074913) from the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Science and ICT.

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Author notes

  1. Ja-Seong Bae and Seung-Hyun Jung contributed equally to this paper.

Authors and Affiliations

  1. Department of Surgery, College of Medicine, The Catholic University of Korea, Seoul, 06591, Republic of Korea

    Ja-Seong Bae & Sohee Lee

  2. College of Medicine, Cancer Research Institute, The Catholic University of Korea, Seoul, 06591, Republic of Korea

    Ja-Seong Bae, Sohee Lee & Chan Kwon Jung

  3. Departmen of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul, 06591, Republic of Korea

    Seung-Hyun Jung

  4. Cancer Evolution Research Center, College of Medicine, The Catholic University of Korea, Seoul, 06591, Republic of Korea

    Seung-Hyun Jung & Yeun-Jun Chung

  5. Department of Diagnostic Pathology and Cytology, Kuma Hospital, Kobe, Hyogo, 650-0011, Japan

    Mitsuyoshi Hirokawa

  6. Department of Pathology, Kameda Medical Center, Kamogawa, Chiba, 296-8602, Japan

    Andrey Bychkov

  7. Department of Surgery, Kuma Hospital, Kobe, Hyogo, 650-0011, Japan

    Akira Miyauchi

  8. College of Medicine, IRCGP, The Catholic University of Korea, Seoul, 06591, Republic of Korea

    Yeun-Jun Chung

  9. Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul, 06591, Republic of Korea

    Yeun-Jun Chung

  10. Department of Hospital Pathology, College of Medicine, The Catholic University of Korea, Seoul, 06591, Republic of Korea

    Chan Kwon Jung

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  1. Ja-Seong Bae
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Contributions

Conceptualization: Chan Kwon Jung, Andrey Bychkov; Methodology: Ja-Seong Bae, Seung-Hyun Jung, Mitsuyoshi Hirokawa, Andrey Bychkov, Akira Miyauchi, Sohee Lee, Yeun-Jun Chung, Chan Kwon Jung; Formal analysis and investigation: Ja-Seong Bae, Seung-Hyun Jung, Yeun-Jun Chung, Chan Kwon Jung; Writing—original draft preparation Ja-Seong Bae, Seung-Hyun Jung, Chan Kwon Jung; Writing—review and editing: Ja-Seong Bae, Seung-Hyun Jung, Mitsuyoshi Hirokawa, Andrey Bychkov, Akira Miyauchi, Sohee Lee, Yeun-Jun Chung, Chan Kwon Jung; Funding acquisition: Chan Kwon Jung; Resources: Ja-Seong Bae, Mitsuyoshi Hirokawa, Akira Miyauchi, Sohee Lee, Yeun-Jun Chung, Chan Kwon Jung; Supervision: Yeun-Jun Chung, Chan Kwon Jung.

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Correspondence to Yeun-Jun Chung or Chan Kwon Jung.

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This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Institutional Review Board of Kuma Hospital (20,181,220–1) and Seoul St. Mary’s Hospital (KC16SISI0709).

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Informed consent was waived by the institutional review board because of the retrospective nature of the study, which used anonymous clinical data.

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Bae, JS., Jung, SH., Hirokawa, M. et al. High Prevalence of DICER1 Mutations and Low Frequency of Gene Fusions in Pediatric Follicular-Patterned Tumors of the Thyroid. Endocr Pathol 32, 336–346 (2021). https://doi.org/10.1007/s12022-021-09688-9

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