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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.

References

  1. Guille JT, Opoku-Boateng A, Thibeault SL, Chen H (2015) Evaluation and management of the pediatric thyroid nodule. Oncologist 20:19-27. https://doi.org/10.1634/theoncologist.2014-0115.

    Article  PubMed  Google Scholar 

  2. Francis GL, Waguespack SG, Bauer AJ, Angelos P, Benvenga S, Cerutti JM, Dinauer CA, Hamilton J, Hay ID, Luster M, Parisi MT, Rachmiel M, Thompson GB, Yamashita S, American Thyroid Association Guidelines Task Force (2015) Management Guidelines for Children with Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid 25:716-759. https://doi.org/10.1089/thy.2014.0460.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Vuong HG, Suzuki A, Na HY, Tuyen PV, Khuy DM, Nguyen HC, Jitpasutham T, Abelardo A, Amano T, Park SY, Jung CK, Hirokawa M, Katoh R, Kakudo K, Bychkov A (2021) Application of the Bethesda System for Reporting Thyroid Cytopathology in the Pediatric Population. Am J Clin Pathol 155:680-689. https://doi.org/10.1093/ajcp/aqaa182.

    Article  PubMed  Google Scholar 

  4. Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, Pacini F, Randolph GW, Sawka AM, Schlumberger M, Schuff KG, Sherman SI, Sosa JA, Steward DL, Tuttle RM, Wartofsky L (2016) 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid 26:1-133. https://doi.org/10.1089/thy.2015.0020.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Vuong HG, Chung DGB, Ngo LM, Bui TQ, Hassell L, Jung CK, Kakudo K, Bychkov A (2021) The Use of the Bethesda System for Reporting Thyroid Cytopathology in Pediatric Thyroid Nodules: A Meta-Analysis. Thyroid. Online ahead of print. https://doi.org/10.1089/thy.2020.0702.

  6. Qian ZJ, Jin MC, Meister KD, Megwalu UC (2019) Pediatric Thyroid Cancer Incidence and Mortality Trends in the United States, 1973-2013. JAMA Otolaryngol Head Neck Surg 145:617-623. https://doi.org/10.1001/jamaoto.2019.0898.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Bernier MO, Withrow DR, Berrington de Gonzalez A, Lam CJK, Linet MS, Kitahara CM, Shiels MS (2019) Trends in pediatric thyroid cancer incidence in the United States, 1998-2013. Cancer 125:2497-2505. https://doi.org/10.1002/cncr.32125.

    Article  PubMed  Google Scholar 

  8. Lloyd RV, Osamura RY, Klöppel G, Rosai J (2017) WHO Classification of Tumors of Endocrine Organs 4th ed. International Agency for Research on Cancer (IARC) Lyon, France pp 65–91

  9. Bai Y, Kakudo K, Jung CK (2020) Updates in the Pathologic Classification of Thyroid Neoplasms: A Review of the World Health Organization Classification. Endocrinol Metab (Seoul) 35:696-715. https://doi.org/10.3803/EnM.2020.807.

    Article  Google Scholar 

  10. Cibas ES, Ali SZ (2017) The 2017 Bethesda System for Reporting Thyroid Cytopathology. Thyroid 27:1341-1346. https://doi.org/10.1089/thy.2017.0500.

    Article  PubMed  Google Scholar 

  11. Cancer Genome Atlas Research N (2014) Integrated genomic characterization of papillary thyroid carcinoma. Cell 159:676-690. https://doi.org/10.1016/j.cell.2014.09.050.

    Article  CAS  Google Scholar 

  12. Ye L, Zhou X, Huang F, Wang W, Qi Y, Xu H, Yang S, Shen L, Fei X, Xie J, Cao M, Zhou Y, Zhu W, Wang S, Ning G, Wang W (2017) The genetic landscape of benign thyroid nodules revealed by whole exome and transcriptome sequencing. Nat Commun 8:15533. https://doi.org/10.1038/ncomms15533.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Xu B, Ghossein RA (2018) The contribution of molecular pathology to the classification of thyroid tumors. Diagn Histopathol (Oxf) 24:87-94. https://doi.org/10.1016/j.mpdhp.2018.02.001.

    Article  Google Scholar 

  14. Jung SH, Kim MS, Jung CK, Park HC, Kim SY, Liu J, Bae JS, Lee SH, Kim TM, Lee SH, Chung YJ (2016) Mutational burdens and evolutionary ages of thyroid follicular adenoma are comparable to those of follicular carcinoma. Oncotarget 7:69638-69648. https://doi.org/10.18632/oncotarget.11922.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Yoo SK, Lee S, Kim SJ, Jee HG, Kim BA, Cho H, Song YS, Cho SW, Won JK, Shin JY, Park do J, Kim JI, Lee KE, Park YJ, Seo JS (2016) Comprehensive Analysis of the Transcriptional and Mutational Landscape of Follicular and Papillary Thyroid Cancers. PLoS Genet 12:e1006239. https://doi.org/10.1371/journal.pgen.1006239.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Lee YA, Im SW, Jung KC, Chung EJ, Shin CH, Kim JI, Park YJ (2020) Predominant DICER1 Pathogenic Variants in Pediatric Follicular Thyroid Carcinomas. Thyroid 30:1120-1131. https://doi.org/10.1089/thy.2019.0233.

    Article  PubMed  Google Scholar 

  17. Wasserman JD, Sabbaghian N, Fahiminiya S, Chami R, Mete O, Acker M, Wu MK, Shlien A, de Kock L, Foulkes WD (2018) DICER1 Mutations Are Frequent in Adolescent-Onset Papillary Thyroid Carcinoma. J Clin Endocrinol Metab 103:2009-2015. https://doi.org/10.1210/jc.2017-02698.

    Article  PubMed  Google Scholar 

  18. Jeon S, Kim Y, Jeong YM, Bae JS, Jung CK (2018) CCND1 Splice Variant as A Novel Diagnostic and Predictive Biomarker for Thyroid Cancer. Cancers (Basel) https://doi.org/10.3390/cancers10110437.

    Article  PubMed Central  Google Scholar 

  19. Kim YJ, Jung SH, Hur EH, Choi EJ, Lee KH, Park HC, Kim HJ, Kwon YR, Park S, Lee SH, Chung YJ, Lee JH (2021) Clinical implications of copy number alteration detection using panel-based next-generation sequencing data in myelodysplastic syndrome. Leuk Res 103:106540. https://doi.org/10.1016/j.leukres.2021.106540.

    Article  CAS  PubMed  Google Scholar 

  20. Robertson J, Jorcyk C, Oxford J (2018) DICER1 Syndrome: DICER1 Mutations in Rare Cancers. Cancers (Basel) 10:143. https://doi.org/10.3390/cancers10050143.

    Article  CAS  Google Scholar 

  21. Vedanayagam J, Chatila WK, Aksoy BA, Majumdar S, Skanderup AJ, Demir E, Schultz N, Sander C, Lai EC (2019) Cancer-associated mutations in DICER1 RNase IIIa and IIIb domains exert similar effects on miRNA biogenesis. Nat Commun 10:3682. https://doi.org/10.1038/s41467-019-11610-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Theotoki EI, Pantazopoulou VI, Georgiou S, Kakoulidis P, Filippa V, Stravopodis DJ, Anastasiadou E (2020) Dicing the Disease with Dicer: The Implications of Dicer Ribonuclease in Human Pathologies. Int J Mol Sci 21:7223. https://doi.org/10.3390/ijms21197223.

    Article  CAS  PubMed Central  Google Scholar 

  23. Ramirez-Moya J, Wert-Lamas L, Riesco-Eizaguirre G, Santisteban P (2019) Impaired microRNA processing by DICER1 downregulation endows thyroid cancer with increased aggressiveness. Oncogene 38:5486-5499. https://doi.org/10.1038/s41388-019-0804-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Chernock RD, Rivera B, Borrelli N, Hill DA, Fahiminiya S, Shah T, Chong A-S, Aqil B, Mehrad M, Giordano TJ, Sheridan R, Rutter MM, Dehner LP, Foulkes WD, Nikiforov YE (2020) Poorly differentiated thyroid carcinoma of childhood and adolescence: a distinct entity characterized by DICER1 mutations. Mod Pathol 33:1264-1274. https://doi.org/10.1038/s41379-020-0458-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Rooper LM, Bynum JP, Miller KP, Lin MT, Gagan J, Thompson LDR, Bishop JA (2020) Recurrent DICER1 Hotspot Mutations in Malignant Thyroid Gland Teratomas: Molecular Characterization and Proposal for a Separate Classification. Am J Surg Pathol 44:826-833. https://doi.org/10.1097/PAS.0000000000001430.

    Article  PubMed  Google Scholar 

  26. Poma AM, Condello V, Denaro M, Torregrossa L, Elisei R, Vitti P, Basolo F (2019) DICER1 somatic mutations strongly impair miRNA processing even in benign thyroid lesions. Oncotarget 10:1785-1797. https://doi.org/10.18632/oncotarget.26639.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Nose V (2020) DICER1 gene alterations in thyroid diseases. Cancer Cytopathol 128:688-689. https://doi.org/10.1002/cncy.22327.

    Article  PubMed  Google Scholar 

  28. Nicolson NG, Murtha TD, Dong W, Paulsson JO, Choi J, Barbieri AL, Brown TC, Kunstman JW, Larsson C, Prasad ML, Korah R, Lifton RP, Juhlin CC, Carling T (2018) Comprehensive Genetic Analysis of Follicular Thyroid Carcinoma Predicts Prognosis Independent of Histology. J Clin Endocrinol Metab 103:2640-2650. https://doi.org/10.1210/jc.2018-00277.

    Article  PubMed  Google Scholar 

  29. Yang J, Sarita-Reyes C, Kindelberger D, Zhao Q (2018) A rare malignant thyroid carcinosarcoma with aggressive behavior and DICER1 gene mutation: a case report with literature review. Thyroid Res 11:11. https://doi.org/10.1186/s13044-018-0055-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Paulsson JO, Wang N, Gao J, Stenman A, Zedenius J, Mu N, Lui W-O, Larsson C, Juhlin CC (2020) GABPA-dependent down-regulation of DICER1 in follicular thyroid tumours. Endocr Relat Cancer 27:295-308. https://doi.org/10.1530/erc-19-0446.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Swierniak M, Pfeifer A, Stokowy T, Rusinek D, Chekan M, Lange D, Krajewska J, Oczko-Wojciechowska M, Czarniecka A, Jarzab M, Jarzab B, Wojtas B (2016) Somatic mutation profiling of follicular thyroid cancer by next generation sequencing. Mol Cell Endocrinol 433:130-137. https://doi.org/10.1016/j.mce.2016.06.007.

    Article  CAS  PubMed  Google Scholar 

  32. Soares P, Povoa AA, Melo M, Vinagre J, Maximo V, Eloy C, Cameselle-Teijeiro JM, Sobrinho-Simoes M (2021) Molecular Pathology of Non-familial Follicular Epithelial-Derived Thyroid Cancer in Adults: From RAS/BRAF-like Tumor Designations to Molecular Risk Stratification. Endocr Pathol 32:44-62. https://doi.org/10.1007/s12022-021-09666-1.

    Article  CAS  PubMed  Google Scholar 

  33. Pstrag N, Ziemnicka K, Bluyssen H, Wesoly J (2018) Thyroid cancers of follicular origin in a genomic light: in-depth overview of common and unique molecular marker candidates. Mol Cancer 17:116. https://doi.org/10.1186/s12943-018-0866-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Macerola E, Proietti A, Basolo F (2020) Noninvasive follicular neoplasm with papillary-like nuclear features (NIFTP): a new entity. Gland Surg 9:S47-S53. https://doi.org/10.21037/gs.2019.12.24.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Vuong HG, Kondo T, Oishi N, Nakazawa T, Mochizuki K, Miyauchi A, Hirokawa M, Katoh R (2017) Paediatric follicular thyroid carcinoma - indolent cancer with low prevalence of RAS mutations and absence of PAX8-PPARG fusion in a Japanese population. Histopathology 71:760-768. https://doi.org/10.1111/his.13285.

    Article  PubMed  Google Scholar 

  36. Beg S, Siraj AK, Jehan Z, Prabakaran S, Al-Sobhi SS, Al-Dawish M, Al-Dayel F, Al-Kuraya KS (2015) PTEN loss is associated with follicular variant of Middle Eastern papillary thyroid carcinoma. Br J Cancer 112:1938-1943. https://doi.org/10.1038/bjc.2015.169.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Smith JR, Marqusee E, Webb S, Nose V, Fishman SJ, Shamberger RC, Frates MC, Huang SA (2011) Thyroid nodules and cancer in children with PTEN hamartoma tumor syndrome. J Clin Endocrinol Metab 96:34-37. https://doi.org/10.1210/jc.2010-1315.

    Article  CAS  PubMed  Google Scholar 

  38. Acquaviva G, Visani M, Repaci A, Rhoden KJ, de Biase D, Pession A, Giovanni T (2018) Molecular pathology of thyroid tumours of follicular cells: a review of genetic alterations and their clinicopathological relevance. Histopathology 72:6-31. https://doi.org/10.1111/his.13380.

    Article  PubMed  Google Scholar 

  39. Jung CK, Jung SH, Jeon S, Jeong YM, Kim Y, Lee S, Bae JS, Chung YJ (2020) Risk Stratification Using a Novel Genetic Classifier Including PLEKHS1 Promoter Mutations for Differentiated Thyroid Cancer with Distant Metastasis. Thyroid 30:1589-1600. https://doi.org/10.1089/thy.2019.0459.

    Article  CAS  PubMed  Google Scholar 

  40. Landa I, Ibrahimpasic T, Boucai L, Sinha R, Knauf JA, Shah RH, Dogan S, Ricarte-Filho JC, Krishnamoorthy GP, Xu B, Schultz N, Berger MF, Sander C, Taylor BS, Ghossein R, Ganly I, Fagin JA (2016) Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers. J Clin Invest 126:1052-1066. https://doi.org/10.1172/JCI85271.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Zhao X, Kotch C, Fox E, Surrey LF, Wertheim GB, Baloch ZW, Lin F, Pillai V, Luo M, Kreiger PA, Pogoriler JE, Linn RL, Russo PA, Santi M, Resnick AC, Storm PB, Hunger SP, Bauer AJ, Li MM (2021) NTRK Fusions Identified in Pediatric Tumors: The Frequency, Fusion Partners, and Clinical Outcome. JCO Precis Oncol 1:204-214. https://doi.org/10.1200/PO.20.00250.

    Article  Google Scholar 

  42. Pekova B, Sykorova V, Dvorakova S, Vaclavikova E, Moravcova J, Katra R, Astl J, Vlcek P, Kodetova D, Vcelak J, Bendlova B (2020) RET, NTRK, ALK, BRAF, and MET Fusions in a Large Cohort of Pediatric Papillary Thyroid Carcinomas. Thyroid 30:1771-1780. https://doi.org/10.1089/thy.2019.0802.

    Article  CAS  PubMed  Google Scholar 

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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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