High Prevalence of Gene Fusions and Copy Number Alterations in Pediatric Radiation Therapy-Induced Papillary and Follicular Thyroid Carcinomas

Childhood cancer survivors and bone marrow transplant recipients treated with radiation therapy (RT) are at increased risk for subsequent thyroid cancer. However, the genetic landscape of pediatric thyroid cancer, both primary and RT-induced, remains poorly defined, as pediatric papillary thyroid ca...

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Bibliographic Details
Published in:	Thyroid (New York, N.Y.) Vol. 32; no. 4; p. 411
Main Authors:	Hess, Jennifer R, Newbern, Dorothee K, Beebe, Kristen L, Walsh, Alexandra M, Schafernak, Kristian T
Format:	Journal Article
Language:	English
Published:	United States 01-04-2022
Subjects:	Adenocarcinoma, Follicular - genetics Adenocarcinoma, Follicular - pathology Adenocarcinoma, Follicular - radiotherapy Adult Carcinoma, Papillary - pathology Child DEAD-box RNA Helicases - genetics DNA Copy Number Variations Gene Fusion Humans Mutation Prevalence Protein-Tyrosine Kinases - genetics Proto-Oncogene Proteins - genetics Proto-Oncogene Proteins B-raf - genetics Ribonuclease III - genetics Thyroid Cancer, Papillary - genetics Thyroid Cancer, Papillary - pathology Thyroid Neoplasms - genetics Thyroid Neoplasms - pathology Thyroid Neoplasms - radiotherapy molecular thyroid cancer radiation pediatrics
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Summary:	Childhood cancer survivors and bone marrow transplant recipients treated with radiation therapy (RT) are at increased risk for subsequent thyroid cancer. However, the genetic landscape of pediatric thyroid cancer, both primary and RT-induced, remains poorly defined, as pediatric papillary thyroid carcinoma (PTC) has been understudied compared with adults and data on pediatric follicular thyroid carcinoma (FTC) are virtually nonexistent. The objective of this study was to characterize and compare the molecular profiles of pediatric RT-induced PTC and FTC cases with primary pediatric thyroid cancers. A total of 41 differentiated thyroid carcinomas (11 RT cases and 30 primary cases) from 37 patients seen at Phoenix Children's Hospital between January 1, 2010 and December 31, 2019 were evaluated by targeted next-generation sequencing and/or BRAF immunohistochemistry. Eighty-six percent (6/7) of RT-PTC harbored a gene fusion (GF) compared with 56% (14/25) of primary PTC; 14% (1/7) of RT-PTC had a single-nucleotide variant (SNV; specifically, a point mutation in the ) compared with 44% (11/25) of primary PTC (all of the latter had the mutation). An exceedingly rare fusion was identified in a child with RT-PTC. With respect to FTC, copy number alterations (CNAs) were seen in 75% (3/4) of RT cases compared with 40% (2/5) of primary cases. None of the RT-FTC had SNVs compared with 100% (5/5) of primary FTC. In children, the molecular profile of subsequent RT-induced thyroid cancers appears to differ from primary (sporadic and syndromic) cases, with a high prevalence of GFs in RT-PTC (similar to PTC occurring after the Chernobyl nuclear reactor accident) and CNAs in RT-FTC. A better understanding of the molecular mechanisms underlying these cancers may lead to more accurate diagnosis, prognosis, and treatment, as some of the genomic alterations are potentially targetable.
ISSN:	1557-9077
DOI:	10.1089/thy.2021.0217