Top

European Journal of Nuclear Medicine and Molecular Imaging

Published in:

Open Access 01-07-2016 | Original Article

Gene signature of the post-Chernobyl papillary thyroid cancer

Authors: Daria Handkiewicz-Junak, Michal Swierniak, Dagmara Rusinek, Małgorzata Oczko-Wojciechowska, Genevieve Dom, Carine Maenhaut, Kristian Unger, Vincent Detours, Tetiana Bogdanova, Geraldine Thomas, Ilya Likhtarov, Roman Jaksik, Malgorzata Kowalska, Ewa Chmielik, Michal Jarzab, Andrzej Swierniak, Barbara Jarzab

Published in: European Journal of Nuclear Medicine and Molecular Imaging | Issue 7/2016

Abstract

Purpose

Following the nuclear accidents in Chernobyl and later in Fukushima, the nuclear community has been faced with important issues concerning how to search for and diagnose biological consequences of low-dose internal radiation contamination. Although after the Chernobyl accident an increase in childhood papillary thyroid cancer (PTC) was observed, it is still not clear whether the molecular biology of PTCs associated with low-dose radiation exposure differs from that of sporadic PTC.

Methods

We investigated tissue samples from 65 children/young adults with PTC using DNA microarray (Affymetrix, Human Genome U133 2.0 Plus) with the aim of identifying molecular differences between radiation-induced (exposed to Chernobyl radiation, ECR) and sporadic PTC. All participants were resident in the same region so that confounding factors related to genetics or environment were minimized.

Results

There were small but significant differences in the gene expression profiles between ECR and non-ECR PTC (global test, p < 0.01), with 300 differently expressed probe sets (p < 0.001) corresponding to 239 genes. Multifactorial analysis of variance showed that besides radiation exposure history, the BRAF mutation exhibited independent effects on the PTC expression profile; the histological subset and patient age at diagnosis had negligible effects. Ten genes (PPME1, HDAC11, SOCS7, CIC, THRA, ERBB2, PPP1R9A, HDGF, RAD51AP1, and CDK1) from the 19 investigated with quantitative RT-PCR were confirmed as being associated with radiation exposure in an independent, validation set of samples.

Conclusion

Significant, but subtle, differences in gene expression in the post-Chernobyl PTC are associated with previous low-dose radiation exposure.

Available only for authorised users

Baverstock K, Egloff B, Pinchera A, Ruchti C, Williams D. Thyroid cancer after Chernobyl. Nature. 1992;359(6390):21–2. doi:10.1038/359021b0.CrossRefPubMed

Kazakov VS, Demidchik EP, Astakhova LN. Thyroid cancer after Chernobyl. Nature. 1992;359(6390):21. doi:10.1038/359021a0.CrossRefPubMed

Tuttle RM, Vaisman F, Tronko MD. Clinical presentation and clinical outcomes in Chernobyl-related paediatric thyroid cancers: what do we know now? What can we expect in the future? Clin Oncol (R Coll Radiol). 2011;23(4):268–75. doi:10.1016/j.clon.2011.01.178.CrossRef

Bounacer A, Wicker R, Caillou B, Cailleux AF, Sarasin A, Schlumberger M, et al. High prevalence of activating ret proto-oncogene rearrangements, in thyroid tumors from patients who had received external radiation. Oncogene. 1997;15(11):1263–73. doi:10.1038/sj.onc.1200206.CrossRefPubMed

Elisei R, Romei C, Vorontsova T, Cosci B, Veremeychik V, Kuchinskaya E, et al. RET/PTC rearrangements in thyroid nodules: studies in irradiated and not irradiated, malignant and benign thyroid lesions in children and adults. J Clin Endocrinol Metab. 2001;86(7):3211–6. doi:10.1210/jcem.86.7.7678.PubMed

Hamatani K, Eguchi H, Ito R, Mukai M, Takahashi K, Taga M, et al. RET/PTC rearrangements preferentially occurred in papillary thyroid cancer among atomic bomb survivors exposed to high radiation dose. Cancer Res. 2008;68(17):7176–82. doi:10.1158/0008-5472.CAN-08-0293.CrossRefPubMed

Kumagai A, Namba H, Saenko VA, Ashizawa K, Ohtsuru A, Ito M, et al. Low frequency of BRAFT1796A mutations in childhood thyroid carcinomas. J Clin Endocrinol Metab. 2004;89(9):4280–4. doi:10.1210/jc.2004-0172.CrossRefPubMed

Lima J, Trovisco V, Soares P, Maximo V, Magalhaes J, Salvatore G, et al. BRAF mutations are not a major event in post-Chernobyl childhood thyroid carcinomas. J Clin Endocrinol Metab. 2004;89(9):4267–71. doi:10.1210/jc.2003-032224.CrossRefPubMed

Nakazawa T, Kondo T, Kobayashi Y, Takamura N, Murata S, Kameyama K, et al. RET gene rearrangements (RET/PTC1 and RET/PTC3) in papillary thyroid carcinomas from an iodine-rich country (Japan). Cancer. 2005;104(5):943–51. doi:10.1002/cncr.21270.CrossRefPubMed

10.

Nikiforov YE, Rowland JM, Bove KE, Monforte-Munoz H, Fagin JA. Distinct pattern of ret oncogene rearrangements in morphological variants of radiation-induced and sporadic thyroid papillary carcinomas in children. Cancer Res. 1997;57(9):1690–4.PubMed

11.

Rabes HM, Demidchik EP, Sidorow JD, Lengfelder E, Beimfohr C, Hoelzel D, et al. Pattern of radiation-induced RET and NTRK1 rearrangements in 191 post-Chernobyl papillary thyroid carcinomas: biological, phenotypic, and clinical implications. Clin Cancer Res. 2000;6(3):1093–103.PubMed

12.

Unger K, Zitzelsberger H, Salvatore G, Santoro M, Bogdanova T, Braselmann H, et al. Heterogeneity in the distribution of RET/PTC rearrangements within individual post-Chernobyl papillary thyroid carcinomas. J Clin Endocrinol Metab. 2004;89(9):4272–9. doi:10.1210/jc.2003-031870.CrossRefPubMed

13.

Tuttle RM, Lukes Y, Onstad L, Lushnikov E, Abrosimov A, Troshin V, et al. ret/PTC activation is not associated with individual radiation dose estimates in a pilot study of neoplastic thyroid nodules arising in Russian children and adults exposed to Chernobyl fallout. Thyroid. 2008;18(8):839–46. doi:10.1089/thy.2008.0072.CrossRefPubMedPubMedCentral

14.

Boltze C, Riecke A, Ruf CG, Port M, Nizze H, Kugler C, et al. Sporadic and radiation-associated papillary thyroid cancers can be distinguished using routine immunohistochemistry. Oncol Rep. 2009;22(3):459–67.PubMed

15.

Ricarte-Filho JC, Li S, Garcia-Rendueles ME, Montero-Conde C, Voza F, Knauf JA, et al. Identification of kinase fusion oncogenes in post-Chernobyl radiation-induced thyroid cancers. J Clin Invest. 2013;123(11):4935–44. doi:10.1172/JCI69766.CrossRefPubMedPubMedCentral

16.

Stein L, Rothschild J, Luce J, Cowell JK, Thomas G, Bogdanova TI, et al. Copy number and gene expression alterations in radiation-induced papillary thyroid carcinoma from Chernobyl pediatric patients. Thyroid. 2010;20(5):475–87. doi:10.1089/thy.2009.0008.CrossRefPubMed

17.

Maenhaut C, Detours V, Dom G, Handkiewicz-Junak D, Oczko-Wojciechowska M, Jarzab B. Gene expression profiles for radiation-induced thyroid cancer. Clin Oncol (R Coll Radiol). 2011;23(4):282–8. doi:10.1016/j.clon.2011.01.509S09.CrossRef

18.

Abend M, Pfeiffer RM, Ruf C, Hatch M, Bogdanova TI, Tronko MD, et al. Iodine-131 dose dependent gene expression in thyroid cancers and corresponding normal tissues following the Chernobyl accident. PLoS One. 2012;7(7), e39103. doi:10.1371/journal.pone.0039103PONE-D-12.CrossRefPubMedPubMedCentral

19.

Dom G, Tarabichi M, Unger K, Thomas G, Oczko-Wojciechowska M, Bogdanova T, et al. A gene expression signature distinguishes normal tissues of sporadic and radiation-induced papillary thyroid carcinomas. Br J Cancer. 2012;107(6):994–1000. doi:10.1038/bjc.2012.302.CrossRefPubMedPubMedCentral

20.

Abend M, Pfeiffer RM, Ruf C, Hatch M, Bogdanova TI, Tronko MD, et al. Iodine-131 dose-dependent gene expression: alterations in both normal and tumour thyroid tissues of post-Chernobyl thyroid cancers. Br J Cancer. 2013;109(8):2286–94. doi:10.1038/bjc.2013.574.CrossRefPubMedPubMedCentral

21.

Edgar R, Domrachev M, Lash AE. Gene Expression Omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res. 2002;30(1):207–10.CrossRefPubMedPubMedCentral

22.

Williams D. Twenty years’ experience with post-Chernobyl thyroid cancer. Best Pract Res Clin Endocrinol Metab. 2008;22(6):1061–73. doi:10.1016/j.beem.2008.09.020.CrossRefPubMed

23.

Detours V, Delys L, Libert F, Weiss Solis D, Bogdanova T, Dumont JE, et al. Genome-wide gene expression profiling suggests distinct radiation susceptibilities in sporadic and post-Chernobyl papillary thyroid cancers. Br J Cancer. 2007;97(6):818–25. doi:10.1038/sj.bjc.6603938.CrossRefPubMedPubMedCentral

24.

Detours V, Wattel S, Venet D, Hutsebaut N, Bogdanova T, Tronko MD, et al. Absence of a specific radiation signature in post-Chernobyl thyroid cancers. Br J Cancer. 2005;92(8):1545–52. doi:10.1038/sj.bjc.6602521.CrossRefPubMedPubMedCentral

25.

Port M, Boltze C, Wang Y, Roper B, Meineke V, Abend M. A radiation-induced gene signature distinguishes post-Chernobyl from sporadic papillary thyroid cancers. Radiat Res. 2007;168(6):639–49. doi:10.1667/RR0968.1.CrossRefPubMed

26.

Ugolin N, Ory C, Lefevre E, Benhabiles N, Hofman P, Schlumberger M, et al. Strategy to find molecular signatures in a small series of rare cancers: validation for radiation-induced breast and thyroid tumors. PLoS One. 2011;6(8), e23581. doi:10.1371/journal.pone.0023581.CrossRefPubMedPubMedCentral

27.

Fuzik M, Prysyazhnyuk A, Shibata Y, Romanenko A, Fedorenko Z, Gulak L, et al. Thyroid cancer incidence in Ukraine: trends with reference to the Chernobyl accident. Radiat Environ Biophys. 2011;50(1):47–55. doi:10.1007/s00411-010-0340-y.CrossRefPubMed

28.

Cancer Genome Atlas Research Network. Integrated genomic characterization of papillary thyroid carcinoma. Cell. 2014;159(3):676–90. doi:10.1016/j.cell.2014.09.050.CrossRef

29.

Frattini M, Ferrario C, Bressan P, Balestra D, De Cecco L, Mondellini P, et al. Alternative mutations of BRAF, RET and NTRK1 are associated with similar but distinct gene expression patterns in papillary thyroid cancer. Oncogene. 2004;23(44):7436–40. doi:10.1038/sj.onc.1207980.CrossRefPubMed

30.

Giordano TJ, Kuick R, Thomas DG, Misek DE, Vinco M, Sanders D, et al. Molecular classification of papillary thyroid carcinoma: distinct BRAF, RAS, and RET/PTC mutation-specific gene expression profiles discovered by DNA microarray analysis. Oncogene. 2005;24(44):6646–56. doi:10.1038/sj.onc.1208822.CrossRefPubMed

31.

Unger K, Zurnadzhy L, Walch A, Mall M, Bogdanova T, Braselmann H, et al. RET rearrangements in post-Chernobyl papillary thyroid carcinomas with a short latency analysed by interphase FISH. Br J Cancer. 2006;94(10):1472–7. doi:10.1038/sj.bjc.6603109.CrossRefPubMedPubMedCentral

32.

Sassolas G, Hafdi-Nejjari Z, Ferraro A, Decaussin-Petrucci M, Rousset B, Borson-Chazot F, et al. Oncogenic alterations in papillary thyroid cancers of young patients. Thyroid. 2012;22(1):17–26. doi:10.1089/thy.2011.0215.CrossRefPubMed

33.

Powell N, Jeremiah S, Morishita M, Dudley E, Bethel J, Bogdanova T, et al. Frequency of BRAF T1796A mutation in papillary thyroid carcinoma relates to age of patient at diagnosis and not to radiation exposure. J Pathol. 2005;205(5):558–64. doi:10.1002/path.1736.CrossRefPubMed

34.

Cardis E, Kesminiene A, Ivanov V, Malakhova I, Shibata Y, Khrouch V, et al. Risk of thyroid cancer after exposure to 131I in childhood. J Natl Cancer Inst. 2005;97(10):724–32. doi:10.1093/jnci/dji129.CrossRefPubMed

35.

Likhtarov I, Thomas G, Kovgan L, Masiuk S, Chepurny M, Ivanova O, et al. Reconstruction of individual thyroid doses to the Ukrainian subjects enrolled in the Chernobyl Tissue Bank. Radiat Prot Dosim. 2013;156(4):407–23. doi:10.1093/rpd/nct096.CrossRef

36.

Langen B, Rudqvist N, Parris TZ, Schuler E, Helou K, Forssell-Aronsson E. Comparative analysis of transcriptional gene regulation indicates similar physiologic response in mouse tissues at low absorbed doses from intravenously administered 211At. J Nucl Med. 2013;54(6):990–8. doi:10.2967/jnumed.112.114462.CrossRefPubMed

37.

Rudqvist N, Schuler E, Parris TZ, Langen B, Helou K, Forssell-Aronsson E. Dose-specific transcriptional responses in thyroid tissue in mice after (131)I administration. Nucl Med Biol. 2015;42(3):263–8. doi:10.1016/j.nucmedbio.2014.11.006.CrossRefPubMed

38.

Fujarewicz K, Jarzab M, Eszlinger M, Krohn K, Paschke R, Oczko-Wojciechowska M, et al. A multi-gene approach to differentiate papillary thyroid carcinoma from benign lesions: gene selection using support vector machines with bootstrapping. Endocrinol Relat Cancer. 2007;14(3):809–26. doi:10.1677/ERC-06-0048.CrossRef

39.

Jarzab B, Wiench M, Fujarewicz K, Simek K, Jarzab M, Oczko-Wojciechowska M, et al. Gene expression profile of papillary thyroid cancer: sources of variability and diagnostic implications. Cancer Res. 2005;65(4):1587–97. doi:10.1158/0008-5472.CAN-04-3078.CrossRefPubMed

40.

Zhou T, Chou JW, Simpson DA, Zhou Y, Mullen TE, Medeiros M, et al. Profiles of global gene expression in ionizing-radiation-damaged human diploid fibroblasts reveal synchronization behind the G1 checkpoint in a G0-like state of quiescence. Environ Health Perspect. 2006;114(4):553–9.CrossRefPubMedPubMedCentral

41.

Baptist M, Lamy F, Gannon J, Hunt T, Dumont JE, Roger PP. Expression and subcellular localization of CDK2 and cdc2 kinases and their common partner cyclin A in thyroid epithelial cells: comparison of cyclic AMP-dependent and -independent cell cycles. J Cell Physiol. 1996;166(2):256–73. doi:10.1002/(SICI)1097-4652(199602)166:2<256::AID-JCP3>3.0.CO;2-O.CrossRefPubMed

42.

Ira G, Pellicioli A, Balijja A, Wang X, Fiorani S, Carotenuto W, et al. DNA end resection, homologous recombination and DNA damage checkpoint activation require CDK1. Nature. 2004;431(7011):1011–7. doi:10.1038/nature02964.CrossRefPubMedPubMedCentral

43.

Dray E, Dunlop MH, Kauppi L, San Filippo J, Wiese C, Tsai MS, et al. Molecular basis for enhancement of the meiotic DMC1 recombinase by RAD51 associated protein 1 (RAD51AP1). Proc Natl Acad Sci U S A. 2011;108(9):3560–5. doi:10.1073/pnas.1016454108.CrossRefPubMedPubMedCentral

44.

Wiese C, Dray E, Groesser T, San Filippo J, Shi I, Collins DW, et al. Promotion of homologous recombination and genomic stability by RAD51AP1 via RAD51 recombinase enhancement. Mol Cell. 2007;28(3):482–90. doi:10.1016/j.molcel.2007.08.027.CrossRefPubMedPubMedCentral

45.

Eschrich S, Zhang H, Zhao H, Boulware D, Lee JH, Bloom G, et al. Systems biology modeling of the radiation sensitivity network: a biomarker discovery platform. Int J Radiat Oncol Biol Phys. 2009;75(2):497–505. doi:10.1016/j.ijrobp.2009.05.056.CrossRefPubMedPubMedCentral

46.

Guo C, Mi J, Brautigan DL, Larner JM. ATM regulates ionizing radiation-induced disruption of HDAC1:PP1:Rb complexes. Cell Signal. 2007;19(3):504–10. doi:10.1016/j.cellsig.2006.08.001.CrossRefPubMed

47.

Lankoff A, Bialczyk J, Dziga D, Carmichael WW, Gradzka I, Lisowska H, et al. The repair of gamma-radiation-induced DNA damage is inhibited by microcystin-LR, the PP1 and PP2A phosphatase inhibitor. Mutagenesis. 2006;21(1):83–90. doi:10.1093/mutage/gel002.CrossRefPubMed

48.

Puustinen P, Junttila MR, Vanhatupa S, Sablina AA, Hector ME, Teittinen K, et al. PME-1 protects extracellular signal-regulated kinase pathway activity from protein phosphatase 2A-mediated inactivation in human malignant glioma. Cancer Res. 2009;69(7):2870–7. doi:10.1158/0008-5472.CAN-08-2760.CrossRefPubMedPubMedCentral

49.

Pastor S, Akdi A, Gonzalez ER, Castell J, Biarnes J, Marcos R, et al. Common genetic variants in pituitary-thyroid axis genes and the risk of differentiated thyroid cancer. Endocrinol Connect. 2012;1(2):68–77. doi:10.1530/EC-12-0017.CrossRef

50.

Demidchik YE, Demidchik EP, Reiners C, Biko J, Mine M, Saenko VA, et al. Comprehensive clinical assessment of 740 cases of surgically treated thyroid cancer in children of Belarus. Ann Surg. 2006;243(4):525–32. doi:10.1097/01.sla.0000205977.74806.0b.CrossRefPubMedPubMedCentral

Title: Gene signature of the post-Chernobyl papillary thyroid cancer
Authors: Daria Handkiewicz-Junak
Michal Swierniak
Dagmara Rusinek
Małgorzata Oczko-Wojciechowska
Genevieve Dom
Carine Maenhaut
Kristian Unger
Vincent Detours
Tetiana Bogdanova
Geraldine Thomas
Ilya Likhtarov
Roman Jaksik
Malgorzata Kowalska
Ewa Chmielik
Michal Jarzab
Andrzej Swierniak
Barbara Jarzab
Publication date: 01-07-2016
Publisher: Springer Berlin Heidelberg
Published in: European Journal of Nuclear Medicine and Molecular Imaging / Issue 7/2016
Print ISSN: 1619-7070
Electronic ISSN: 1619-7089
DOI: https://doi.org/10.1007/s00259-015-3303-3

At a glance: The STEP trials

Springer Medicine

Gene signature of the post-Chernobyl papillary thyroid cancer

Abstract

Purpose

Methods

Results

Conclusion

At a glance: The STEP trials

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 7/2016

Dual-phase amyloid PET: hitting two birds with one stone

Mapping brain morphological and functional conversion patterns in predementia late-onset bvFTD

Erratum to: Vesicular monoamine transporter protein expression correlates with clinical features, tumor biology, and MIBG avidity in neuroblastoma: a report from the Children’s Oncology Group

Bone scintigraphy in tophaceous gout

Reduction in camera-specific variability in [123I]FP-CIT SPECT outcome measures by image reconstruction optimized for multisite settings: impact on age-dependence of the specific binding ratio in the ENC-DAT database of healthy controls

Imaging characteristic of dual-phase 18F-florbetapir (AV-45/Amyvid) PET for the concomitant detection of perfusion deficits and beta-amyloid deposition in Alzheimer’s disease and mild cognitive impairment