title: 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.
authors.forename: Jan Christian
authors.initials: JC
authors.lastname: Kaiser
authors.affiliation: Boris-Blacher-Str. 14, 80939 München, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Meckbach
authors.forename: Markus
authors.initials: M
authors.lastname: Eidemüller
authors.affiliation: Helmholtz Zentrum München, Research Unit Radiation Cytogenetics, 85764 Neuherberg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Selmansberger
authors.affiliation: Helmholtz Zentrum München, Research Unit Radiation Cytogenetics, 85764 Neuherberg, Germany.
authors.forename: Kristian
authors.initials: K
authors.lastname: Unger
authors.affiliation: National Academy of Medical Sciences of the Ukraine, Institute of Endocrinology and Metabolism, 254114 Kyiv, Ukraine.
authors.forename: Viktor
authors.initials: V
authors.lastname: Shpak
authors.affiliation: Johannes Gutenberg Universität, Institut für Medizinische Biometrie Epidemiologie und Informatik, 55131 Mainz, Germany and.
authors.forename: Maria
authors.initials: M
authors.lastname: Blettner
authors.affiliation: Helmholtz Zentrum München, Research Unit Radiation Cytogenetics, 85764 Neuherberg, Germany.
authors.forename: Horst
authors.initials: H
authors.lastname: Zitzelsberger
authors.affiliation: RADRISK, 83727 Schliersee, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Jacob
mesh_terms: D000293:Adolescent; D000328:Adult; D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000235:genetics; D002277:Carcinoma / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D002291:Carcinoma, Papillary; D047852:Chernobyl Nuclear Accident; D002648:Child; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects; D006801:Humans; D008297:Male; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis* / Q000235:genetics; D009381:Neoplasms, Radiation-Induced / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D000077273:Thyroid Cancer, Papillary; D013961:Thyroid Gland / Q000473:pathology / Q000528:radiation effects; D013964:Thyroid Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; D008869:Microtubule-Associated Proteins; C109878:cytoplasmic linker protein 115