Jonathan D Wasserman1,2, Nelly Sabbaghian3, Somayyeh Fahiminiya4, Rose Chami5, Ozgur Mete6, Meryl Acker1, Mona K Wu3,7, Adam Shlien5,8, Leanne de Kock3,7, William D Foulkes3,4,7. 1. Division of Endocrinology, The Hospital for Sick Children, Toronto, Ontario, Canada. 2. Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada. 3. Lady Davis Institute, Segal Cancer Centre, Jewish General Hospital, Montreal, Quebec, Canada. 4. Department of Medical Genetics, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada. 5. Division of Pathology, Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada. 6. Department of Pathology, University Health Network, University of Toronto, Toronto, Ontario, Canada. 7. Department of Human Genetics, McGill University, Montreal, Quebec, Canada. 8. Program in Genetics and Genome Biology, SickKids Research Institute, Toronto, Ontario, Canada.
Abstract
Context: Papillary thyroid carcinoma (PTC) is a common malignancy in adolescence and is molecularly and clinically distinct from adult PTC. Mutations in the DICER1 gene are associated with thyroid abnormalities, including multinodular goiter and differentiated thyroid carcinoma. Objective: In this study, we sought to characterize the prevalence of DICER1 variants in pediatric PTC, specifically in tumors without conventional PTC oncogenic alterations. Patients: Patients (N = 40) who underwent partial or total thyroidectomy and who were <18 years of age at the time of surgery were selected. Design: The 40 consecutive thyroidectomy specimens (30 malignant, 10 benign) underwent genotyping for 17 PTC-associated variants, as well as full sequencing of the exons and exon-intron boundaries of DICER1. Results: Conventional alterations were found in 12 of 30 (40%) PTCs (five BRAFV600E, three RET/PTC1, four RET/PTC3). Pathogenic DICER1 variants were identified in 3 of 30 (10%) PTCs and in 2 of 10 (20%) benign nodules, all of which lacked conventional alterations and did not recur during follow-up. DICER1 alterations thus constituted 3 of 18 (16.7%) PTCs without conventional alterations. The three DICER1-mutated carcinomas each had two somatic DICER1 alterations, whereas two follicular-nodular lesions arose in those with germline DICER1 mutations and harbored characteristic second somatic RNase IIIb "hotspot" mutations. Conclusions: DICER1 is a driver of pediatric thyroid nodules, and DICER1-mutated PTC may represent a distinct class of low-risk malignancies. Given the prevalence of variants in children, we advocate for inclusion of DICER1 sequencing and gene dosage determination in molecular analysis of pediatric thyroid specimens.
Context:Papillary thyroid carcinoma (PTC) is a common malignancy in adolescence and is molecularly and clinically distinct from adult PTC. Mutations in the DICER1 gene are associated with thyroid abnormalities, including multinodular goiter and differentiated thyroid carcinoma. Objective: In this study, we sought to characterize the prevalence of DICER1 variants in pediatric PTC, specifically in tumors without conventional PTC oncogenic alterations. Patients: Patients (N = 40) who underwent partial or total thyroidectomy and who were <18 years of age at the time of surgery were selected. Design: The 40 consecutive thyroidectomy specimens (30 malignant, 10 benign) underwent genotyping for 17 PTC-associated variants, as well as full sequencing of the exons and exon-intron boundaries of DICER1. Results: Conventional alterations were found in 12 of 30 (40%) PTCs (five BRAFV600E, three RET/PTC1, four RET/PTC3). Pathogenic DICER1 variants were identified in 3 of 30 (10%) PTCs and in 2 of 10 (20%) benign nodules, all of which lacked conventional alterations and did not recur during follow-up. DICER1 alterations thus constituted 3 of 18 (16.7%) PTCs without conventional alterations. The three DICER1-mutated carcinomas each had two somatic DICER1 alterations, whereas two follicular-nodular lesions arose in those with germline DICER1 mutations and harbored characteristic second somatic RNase IIIb "hotspot" mutations. Conclusions: DICER1 is a driver of pediatric thyroid nodules, and DICER1-mutated PTC may represent a distinct class of low-risk malignancies. Given the prevalence of variants in children, we advocate for inclusion of DICER1 sequencing and gene dosage determination in molecular analysis of pediatric thyroid specimens.
Authors: Sule Canberk; Joana C Ferreira; Luísa Pereira; Rui Batısta; Andre F Vieira; Paula Soares; Manuel Sobrinho Simões; Valdemar Máximo Journal: Eur Thyroid J Date: 2020-08-06
Authors: Rebecca D Chernock; Barbara Rivera; Nicla Borrelli; D Ashley Hill; Somayyeh Fahiminiya; Tasha Shah; Anne-Sophie Chong; Barina Aqil; Mitra Mehrad; Thomas J Giordano; Rachel Sheridan; Meilan M Rutter; Louis P Dehner; William D Foulkes; Yuri E Nikiforov Journal: Mod Pathol Date: 2020-01-14 Impact factor: 7.842