Integration of a radiation biomarker into modeling of thyroid carcinogenesis and post-Chernobyl risk assessment

Abstract

Strong evidence for the statistical association between radiation exposure and disease has been produced for thyroid cancer by epidemiological studies after the Chernobyl accident. However, limitations of the epidemiological approach in order to explore health risks especially at low doses of radiation appear obvious. Statistical fluctuations due to small case numbers dominate the uncertainty of risk estimates. Molecular radiation markers have been searched extensively to separate radiation-induced cancer cases from sporadic cases. The overexpression of the CLIP2 gene is the most promising of these markers. It was found in the majority of papillary thyroid cancers (PTCs) from young patients included in the Chernobyl tissue bank. Motivated by the CLIP2 findings we propose a mechanistic model which describes PTC development as a sequence of rate-limiting events in two distinct paths of CLIP2-associated and multistage carcinogenesis. It integrates molecular measurements of the dichotomous CLIP2 marker from 141 patients into the epidemiological risk analysis for about 13 000 subjects from the Ukrainian-American cohort which were exposed below age 19 years and were put under enhanced medical surveillance since 1998. For the first time, a radiation risk has been estimated solely from marker measurements. Cross checking with epidemiological estimates and model validation suggests that CLIP2 is a marker of high precision. CLIP2 leaves an imprint in the epidemiological incidence data which is typical for a driver gene. With the mechanistic model, we explore the impact of radiation on the molecular landscape of PTC. The model constitutes a unique interface between molecular biology and radiation epidemiology.

Lessons from Fukushima: Latest Findings of Thyroid Cancer After the Fukushima Nuclear Power Plant Accident

“…So far, no reliable molecular signature has been established. An analysis of Chernobyl cases reported that CLIP2 , which is located on chromosome 7q11.23, is specifically amplified in a subset of cases compared to unexposed PTCs, and that on immunohistochemistry, a significant difference in the level of protein expression is observed ( 39 ). Further studies, including analyses with more advanced technologies such as next-generation sequencing, are necessary to identify molecular signatures associated with radiation exposure.…”

Demographic and onco-epidemiological situation in radioactive contaminated territory of Zhytomyr Oblast

“…In the genesis of oncological diseases, a significant role may belong to irradiation of the population (Kaiser et al, 2016). Mean total doses of internal and external irradiation of the population of the affected regions of Zhytomyr Oblast equaled 1.…”

Thyroid Cancer Incidence around the Belgian Nuclear Sites, 2000–2014

“…Recently, the investigation of papillary thyroid carcinoma from a cohort revealed an overexpression of the CLIP2 gene among young patients exposed to the post-Chernobyl radioiodine fallout at a very young age [ 19 ]. More recently, mechanistic models were proposed to explore the impact of radiation on the molecular landscape of papillary thyroid carcinoma [ 20 , 21 ]. The findings point to a function of CLIP2 as a driver gene in radiation-induced papillary thyroid carcinoma.…”