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

Carcinogenesis, Jul 2015

Selmansberger, Martin, Kaiser, Jan Christian, Hess, Julia, Güthlin, Denise, Likhtarev, I., Shpak, Victor, Tronko, Mykola, Brenner, Alina, Abend, Michael, Blettner, Maria, et al.

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

Carcinogenesis Dose-dependent expression of CLIP2 in post-Chernobyl papillary thyroid carcinomas Martin Selmansberge 2 Jan Christian Kaise 1 Julia Hess 2 Denise Güthlin 1 I.Likhtarev 0 Victor Shpak 6 Mykola Tronko 6 Alina Brenner 5 Michael Abend 4 Maria Blettne 3 Kristian Unger 2 Peter Jacob 1 Horst Zitzelsberge 2 0 Ry,adiation Protection Institute, Ukrainian Academy of Technological Sciences , 04050 Kyiv , Ukraine 1 dInstitute of Radiation Protection, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH , 85674 Neuherberg, German 2 Research Unit Radiation Cytogenetics an 3 dInstitut für Medizinische Biometrie, Epidemiologie und Informatik (IMBEI), Johannes Gutenberg Universität , 55131 Mainz , Germany 4 Bundeswehr Institute of Radiobiology , 80937 Munich , Germany an 5 R,adiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, NCI , Bethesda, MD 20892 , USA 6 ,Institute of Endocrinology and Metabolism, National Academy of Medical Sciences of the Ukraine , 254114 Kyiv , Ukraine A previous study on papillary thyroid carcinomas (PTC) in young patients who were exposed t13o1iodine from the Chernobyl fallout revealed an exclusive gain of chromosomal band 7q11.23 in exposed cases compared to an age-matched control cohort. CLIP2, a gene located within band 7q11.23 was shown to be differentially expressed between exposed and nonexposed cases at messenger RNA and protein level. Therefore, a standardized procedure for CLIP2 typing of PTCs has been developed in a follow-up study. Here we used CLIP2 typing data on 117 post-Chernobyl PTCs from two cohorts of exposed patients with individual dose estimates and 24 non-exposed controls to investigate a possible quantitative dose-response relationship of the CLIP2 marker. The 'Genrisk-T' cohort consisted of 45 PTCs and the 'UkrAm' cohort of 72 PTCs. Both cohorts differed in mean dose (0.59 Gy Genrisk-T, 1.2 Gy UkrAm) and mean age at exposure (AaE) (2 years Genrisk-T, 8 years UkrAm), whilst the median latency (16 years Genrisk-T, 18 years UkrAm) was comparable. We analyzed the association between the binary CLIP2 typing and continuous thyroid dose with logistic regression. A clear positive dose-response relationship was found for young PTC cases [age at operation (AaO) < 20 years, AaE < 5 years]. In the elder age group a higher proportion of sporadic tumors is assumed due to a negligible dose response, suggesting different molecular mechanisms in sporadic and radiation-induced cases. This is further supported by the association of elder patients (AaO > 20 years) with positivity for BRAF V600E mutation. Introduction Numerous epidemiological studies have shown a dramatic under the age of 18 at the time of the reactor accident in April increase in papillary thyroid carcinoma (PTC) incidence among 1986, 6848 thyroid cancer cases have been detected between young children exposed to radiation after the Chernobyl accident. 1991 and 2005 (8). To enable comprehensive biological studies on The increase is related to a radiation dose in the thyroid gland this cancer type, which appeared at first in the aftermath of the mainly from ingested 131iodine (I-131) (1–7). Among children and accident, the Chernobyl Tissue Bank (CTB) provides a systematic adolescents from the affected geographical regions, who were collection of thyroid tumors from residents in the contaminated Abbreviations regions of Ukraine and Russia w(ww.chernobyltissuebank.com) since 1998. A  screening study of selected children and adol-es cents exposed to I-131 has been initiated by a Ukrainian–US consortium (9). The resulting UkrAm cohort study included only subjects with individual measurements of the thyroid activity. For each cohort member, the thyroid mass and an intake fun-c tion for I-131 were estimated for reconstruction of individual thyroid doses which amounted to 0.66 Gy on average1(0). Two radio-epidemiological studies on the UkrAm cohort demo-n strated a significantly increased thyroid cancer risk in relation to the I-131 dose. During the first screening phase 1998–2000 45 prevalent cases (43 PTCs, two follicular carcinoma) were detected and operated at a mean age of 16 years. The dose-response for prevalence of thyroid cancer was linear with an excess relative risk of 5.3 per Gy (95% confidence interval: 1.7, 28)4 (). For the 61 incidental PTCs, which were detected in three screening phases from 2001–2008, the mean age at operation (AaO) was 24 years and the dose-response analysis resulted in a markedly lower risk of 1.6 per Gy (95% confidence interval: 0.3, 5.4)6(). The availability of tissue samples through the CTB promoted a huge number of molecular studies including investigations of specific RET/PTC gene rearrangements [reviewed in1(1)], radiation-associated gene alterations as determined by global gene expression analyses (12–16) and global genomic copy number analysis (17,18). In particular, several studies demonstrated gene expressions related (...truncated)


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Selmansberger, Martin, Kaiser, Jan Christian, Hess, Julia, Güthlin, Denise, Likhtarev, I., Shpak, Victor, Tronko, Mykola, Brenner, Alina, Abend, Michael, Blettner, Maria, Unger, Kristian, Jacob, Peter, Zitzelsberger, Horst. Dose-dependent expression of CLIP2 in post-Chernobyl papillary thyroid carcinomas, Carcinogenesis, 2015, pp. 748-756, Volume 36, Issue 7, DOI: 10.1093/carcin/bgv043