Oncogenic rearrangements driving ionizing radiation–associated human cancer

Abstract

The Chernobyl nuclear disaster has caused a remarkable increase in radiation-induced papillary thyroid carcinoma in children and young adults. In this issue of the JCI, Ricarte-Filho and colleagues demonstrate that chromosomal rearrangements are the oncogenic "drivers" in most postChernobyl carcinomas and that they often lead to unscheduled activation of the MAPK signaling pathway. These findings represent a major step forward in our understanding of radiation-induced carcinogenesis and suggest various hypotheses about the mechanisms underlying the formation and selection of gene rearrangements during cancer cell evolution.

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].…”

Radiation signatures in childhood thyroid cancers after the Chernobyl accident: Possible roles of radiation in carcinogenesis

“…The RET/PTC1 as well as RET/PTC2 rearrangements were also reported . It is well established that RET / PTC1 gene rearrangement is the most prevailing genetic alteration in childhood PTCs after the Chernobyl accident overall …”