Dose-dependent expression of CLIP2 in post-Chernobyl papillary thyroid carcinomas

Selmansberger, Martin; Kaiser, Jan Christian; Heß, Julia; Güthlin, Denise; Likhtarev, I.A.; Shpak, Victor; Тronko, М.D.; Brenner, Alina V.; Abend, Michael; Blettner, Maria; Unger, Kristian; Jacob, Peter; Zitzelsberger, Horst

doi:10.1093/carcin/bgv043

Cited by 26 publications

(30 citation statements)

References 34 publications

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“…In Figure 2, the estimate for P epi at attained age 17 years is compared with the response P mol for AaO < 20 years of Selmansberger et al (16). For young patients, the probabilities exhibit similar dose responses in view of their uncertainties.…”

Section: Resultsmentioning

confidence: 99%

“…In contrast to the above-mentioned epidemiological UkrAm cohort, our tumor cohort of 141 PTC patients from the CTB with individual CLIP2 status and TDose10 estimates (27) has been formed previously by Selmansberger et al (16). They have joined the discovery cohort Genrisk-T with validation cohorts Genrisk-T plus and UkrAm (CTB tumors only) which were investigated in earlier exploratory studies related to the CLIP2 marker (14,15).…”

Section: Methodsmentioning

confidence: 99%

“…Conceptual model for the development of sporadic PTC from multi-stage carcinogenesis (MSC) (upper path) and sporadic or radiation-induced PTC from CLIP2-associated carcinogenesis (C2C) (lower path), path-specific case shares are calculated from the preferred mechanistic model based on 141 PTC patients used in Selmansberger et al (16), a mathematical implementation of the model is given in the Supplementary Material, available at Carcinogenesis Online, black arrows with Greek symbols denote transition rates between boxes, jagged yellow arrow denotes radiation action on rate µ, boxes represent cells with molecular changes discussed in Selmansberger et al (18) for ( a ) point mutations of genes BRAF, RAS or gene rearrangements (e.g. RET/PTC) (Supplementary Table 10, available at Carcinogenesis Online), ( b ) copy number alterations (MSC) or CLIP2-associated aneuploidy (Supplementary Table 9, available at Carcinogenesis Online), ( c ) transcriptomic subtypes ‘RAS-like’, ‘intermediate RAS-BRAF’, ‘BRAF-like’ (Supplementary Table 10, available at Carcinogenesis Online) and ( d ) novel transcriptomic subtype (radiation-related) (Supplementary Table 10, available at Carcinogenesis Online).…”

Section: Methodsmentioning

confidence: 99%

“…A numerical value for the number N b of thyroblasts is difficult to estimate. In young patients, the CLIP2 marker is induced by radiation, whereas in a small number of older patients the CLIP2 marker appears also sporadically (16). We assume that C2C occurs in a simple two-stage model with different parameter dependencies for radiation-induced C2C (rC2C) and sporadic C2C (sC2C).…”

Section: Methodsmentioning

confidence: 99%

“…Radiation-related CLIP2 overexpression has been validated with independent samples from cohorts Genrisk-T and UkrAm at protein level using a dedicated protocol which combined immunohistochemistry with digital image analysis (15). Results from both studies suggest that CLIP2 overexpression can be applied as a dichotomous biomarker to decide on the sporadic or radiation-associated origin of a PTC in young patients operated below 20 years (16). …”

Section: Introductionmentioning

confidence: 99%

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

Kaiser

Meckbach²,

Eidemüller

et al. 2016

CARCIN

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Kaiser

Meckbach²,

Eidemüller

et al. 2016

CARCIN

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Doses of Ukrainian female clean-up workers with diagnosed breast cancer

Chumak

Klymenko

Zitzelsberger

et al. 2018

Radiat Environ Biophys

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The Chernobyl reactor accident in 1986 has caused significant exposure to ionizing radiation of the Ukrainian population, in particular clean-up workers and evacuees from the exclusion zones. A study aiming at the discovery of radiation markers of the breast cancer was conducted from 2008 to 2015 within a collaborative project by HZM, LMU, and NRCRM. In this study, post-Chernobyl breast cancer cases both in radiation-exposed female patients diagnosed at age less than 60 from 1992 to 2014 and in non-exposed controls matched for residency, tumor type, age at diagnosis, TNM classification as well as tumor grading were investigated for molecular changes with special emphasis to copy number alterations and miRNA profiles. Cancer registry and clinical archive data were used to identify 435 breast cancer patients among female clean-up workers and 14 among evacuees from highly contaminated territories as candidates for the study. Of these, 129 breast cancer patients fit study inclusion criteria and were traced for individual reconstruction of the target organ (breast) doses. The doses were estimated for 71 exposed cases (clean-up workers and evacuees from which biomaterial was available for molecular studies and who agreed to participate in a dosimetric interview) by the use of the well-established RADRUE method, which was adjusted specifically for the assessment of breast doses. The results of 58 female clean-up workers showed a large inter-individual variability of doses in a range of about five orders of magnitude: from 0.03 to 929 mGy, with median of 5.8 mGy. The study provides the first quantitative estimate of exposures received by female clean-up workers, which represent a limited but very important group of population affected by the Chernobyl accident. The doses of 13 women evacuated after the accident who did not take part in the clean-up activities (from 4 to 45 mGy with median of 19 mGy) are in line with the previous estimates for the evacuees from Pripyat and the 30-km zone.

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Somatic Genomics of Childhood Thyroid Cancer

Thomas

2017

Thyroid Cancer and Nuclear Accidents: Long-Term Aftereffects of Chernobyl and Fukushima

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Dose-dependent expression of CLIP2 in post-Chernobyl papillary thyroid carcinomas

Abstract: SummaryThis study showed a clear dose-response relationship for the CLIP2 radiation marker in post-Chernobyl papillary thyroid carcinoma cohorts for young patients and hints to different molecular mechanisms in tumors induced at low doses compared to moderate/high doses.

Cited by 26 publications

References 34 publications

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

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

Doses of Ukrainian female clean-up workers with diagnosed breast cancer

Somatic Genomics of Childhood Thyroid Cancer

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