Identification of kinase fusion oncogenes in post-Chernobyl radiation-induced thyroid cancers

Abstract

Exposure to ionizing radiation during childhood markedly increases the risk of developing papillary thyroid cancer. We examined tissues from 26 Ukrainian patients with thyroid cancer who were younger than 10 years of age and living in contaminated areas during the time of the Chernobyl nuclear reactor accident. We identified nonoverlapping somatic driver mutations in all 26 cases through candidate gene assays and next-generation RNA sequencing. We found that 22 tumors harbored fusion oncogenes that arose primarily through intrachromosomal rearrangements. Altogether, 23 of the oncogenic drivers identified in this cohort aberrantly activate MAPK signaling, including the 2 somatic rearrangements resulting in fusion of transcription factor ETS variant 6 (ETV6) with neurotrophic tyrosine kinase receptor, type 3 (NTRK3) and fusion of acylglycerol kinase (AGK) with BRAF. Two other tumors harbored distinct fusions leading to overexpression of the nuclear receptor PPARγ. Fusion oncogenes were less prevalent in tumors from a cohort of children with pediatric thyroid cancers that had not been exposed to radiation but were from the same geographical regions. Radiation-induced thyroid cancers provide a paradigm of tumorigenesis driven by fusion oncogenes that activate MAPK signaling or, less frequently, a PPARγ-driven transcriptional program.

A Case of Primary Mammary Analog Secretory Carcinoma (MASC) of the Thyroid Masquerading as Papillary Thyroid Carcinoma: Potentially More than a One Off

“…Exposure history is relevant, because up to 14.5 % of patients with ETV6-NTRK3 fusion papillary thyroid carcinoma have been exposed to a high level of environmental radiation such as subsequent to the 1986 Chernobyl nuclear reactor accident [18]. In sporadic papillary thyroid carcinoma, the incidence of EVT6-NTRK3 gene fusion ranges from approximately 1.2-4 % [19][20][21]. However, the prevalence may be higher in children and adolescents based on a recent small series of 28 patients aged 6-18 years with no history of radiation exposure and with ''papillary thyroid carcinoma'' whose tumors were assessed by a targeted next-generation sequencing panel (ThyroSeq version 2) revealing a 26 % rate of NTRK fusions (7/27 cases; 5 comprising the ETV6-NTRK3 fusion) [22].…”

“…However, the prevalence may be higher in children and adolescents based on a recent small series of 28 patients aged 6-18 years with no history of radiation exposure and with ''papillary thyroid carcinoma'' whose tumors were assessed by a targeted next-generation sequencing panel (ThyroSeq version 2) revealing a 26 % rate of NTRK fusions (7/27 cases; 5 comprising the ETV6-NTRK3 fusion) [22]. Notably, the ETV6-NTRK3 fusion in the radiation and sporadic papillary thyroid carcinomas differs from the ETV6-NTRK3 fusion reported in most MASC in the exon breakpoint in the NTRK3 gene (exon 14 in thyroid tumors and exon 13 in MASC of salivary glands) [1,20,21]. However, Skalova and colleagues recently reported a case of MASC of the salivary glands with the same fusion breakpoints as found in ''papillary thyroid carcinoma'' with the ETV6-NTRK3 fusion [8].…”

“…Morphologically, ''papillary thyroid carcinoma'' associated with the EVT6-NTRK3 fusion is described most commonly as either the follicular variant or mixed classic and follicular variants of papillary thyroid carcinoma [19][20][21]. Further descriptions of the histomorphology of these tumors are generally not provided other than to note a solid component in some cases, especially those associated with radiation exposure.…”

“…Importantly, the studies of ETV6-NTRK3 fusion positive PTC do not provide immunohistochemical staining results of the tumors with the antibodies we used and which would be expected to distinguish true PTC from MASC (e.g. antibodies to thyroglobulin, TTF-1, mammoglobin, GATA3, or S-100 protein) [18][19][20][21][22].…”

Systematic screening after Chernobyl: Insights on radiation‐induced thyroid cancer

“…In a study of 26 thyroid cancers diagnosed in a cohort of Ukrainian patients, known and novel gene rearrangements proved to be the oncogenic driver for 22 (84%) of the cancers. 6 RET/PTC3 rearrangements often are associated with the solid variant of papillary thyroid cancer; and, in general, tumors diagnosed shortly after radiation exposure are more likely to have gene rearrangements compared with those that are diagnosed after a long latency period (range, 9-12 years). 3 Although dose-related effects likely contribute to the variable histology observed, and the short latency period is reflective of the rapid carcinogenic effects of gene rearrangements on the thyroid, alternatively, there may be a yet-to-be-defined genetic predisposition that modifies the increased thyroid cancer risk.…”