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Comprehensive analysis for detecting radiation-specific molecules expressed during radiation-induced rat thyroid carcinogenesis.

ABSTRACT: Although the association between radiation exposure and thyroid carcinogenesis is epidemiologically evident, 'true' radiation-induced cancers cannot be identified from biological evidence of radiation-associated cases. To assess the individual risk for thyroid cancer due to radiation exposure, we aimed to identify biomarkers that are specifically altered during thyroid carcinogenesis after irradiation in a time-dependent manner in an animal model. Thyroid glands were obtained from rats (n = 175) at 6-16 months after local X-ray (0.1-4 Gy) irradiation of the neck at 7 weeks of age. The gene expression profile in thyroid glands was comprehensively analyzed using RNA microarray. Subsequently, the expression levels of the genes of interest were verified using droplet digital PCR (ddPCR). The expression level of candidate genes as biomarkers for irradiated thyroid was examined in a randomized, controlled, double-blind validation study (n = 19) using ddPCR. The incidence of thyroid cancer increased in a dose- and time-dependent manner and was 33% at 16 months after irradiation with 4 Gy. The Ki-67 labeling index in non-tumorous thyroid was significantly higher in the exposed group than in the control. Comprehensive analysis identified radiation-dependent alteration in 3329 genes. Among them, ddPCR revealed a stepwise increase in CDKN1A expression from early pre-cancerous phase in irradiated thyroid compared to that in the control. The irradiated thyroids were accurately distinguished (positive predictive value 100%, negative predictive value 69%) using 11.69 as the cut-off value for CDKN1A/β-actin. Thus, CDKN1A expression can be used as a biomarker for irradiated thyroid glands at the pre-cancerous phase.

SUBMITTER: Kurohama H

PROVIDER: S-EPMC8114207 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Radiation is a well-described risk factor for differentiated thyroid carcinoma (DTC). Although the natural history of DTC following nuclear disasters and in healthcare workers with chronic radiation exposure (RE) has been described, little is known about DTC following short-term exposure to therapeutic medical radiation for benign disease. This study compares DTC morphology and outcomes in patients with and without a prior history of therapeutic external RE.A retrospective review was performed of patients with DTC treated at The University of Chicago between 1951 and 1987, with a median follow-up of 27 years (range 0.3-60 years). Patients were classified as either having (RE+) or not having (RE-) a history of therapeutic RE. Variables examined included sex, age at RE, dose of RE, indication for RE, DTC histology, and outcome. Morphology was determined by blinded retrospective review of all available histologic slides. Outcomes were assessed using Cox proportional hazards model and Kaplan-Meier curves.Of 257 DTC patients, 165 (64%) were RE- and 92 (36%) were RE+, with males comprising a greater proportion of the RE+ group (43.5% vs. 27.3%; p?=?0.01). A total of 94.2% of DTC cases were classic papillary cancers; histology did not differ between RE+ and RE- cohorts (p?=?0.73). RE was associated with an increased median overall survival (OS; 43 years vs. 38 years; hazard ratio [HR]?=?0.55 [confidence interval (CI) 0.34-0.89]; p?=?0.01). Survival for males in the RE- group was significantly worse than it was for RE- females (HR?=?1.78 [CI 1.05-3.03]; p?=?0.03) or RE+ males (HR?=?2.98 [CI 1.39-6.38]; p?=?0.01). Recurrence did not differ between the RE+ and RE- groups (HR?=?0.85 [CI 0.52-1.41]; p?=?0.54), nor did DTC-specific mortality (HR?=?0.54 [CI 0.21-1.37]; p?=?0.20).While DTC following RE has historically been considered a more aggressive variant than DTC in the absence of RE, the present data indicate that RE+ DTC is associated with better OS than RE- DTC, especially for males. Additionally, recent reports are confirmed of equivalent rates of thyroid cancer recurrence. These results warrant further investigation into the factors underlying this unexpected finding.

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Comprehensive analysis for detecting radiation-specific molecules expressed during radiation-induced rat thyroid carcinogenesis.

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