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Molecular Genetics of Childhood Papillary Thyroid Carcinomas After Irradiation: High Prevalence of RET Rearrangement

  • Conference paper
Book cover Genes and Environment in Cancer

Part of the book series: Recent Results in Cancer Research ((RECENTCANCER,volume 154))

Abstract

Epidemiological studies have revealed a connection between thyroid carcinogenesis and a history of radiation. The molecular mechanisms involed are not well understood. It has been claimed that RAS, p53 or GSP mutations and RET or TRK rearrangements might play a role in adult thyroid tumors. In childhood, the thyroid gland is particularly sensitive to ionizing radiation. The reactor accident in Chernobyl provided a unique chance to study molecular genetic aberrations in a cohort of children who developed papillary thyroid carcinomas after a short latency time after exposure to high doses of radioactive iodine isotopes. According to the concepts of molecular genetic epidemiology, exposure to a specific type of irradiation might result in a typical molecular lesion. Childhood papillary thyroid tumors after Chernobyl exhibit a high prevalence of RET rearrangement as almost the only molecular alteration. The majority showed RET/PTC3 (i.e., ELE/RET rearrangements), including several subtypes. Less frequently, RET/PTC1 (i.e., H4/RET rearrangements), and a novel type (RET/PTC5, i.e., RFG5/RET) were observed. Proof of reciprocal transcripts suggests that a balanced intrachromosomal inversion leads to this rearrangement. Breakpoint analyses revealed short homologous nucleotide stretches at the fusion points. In all types of rearrangement, the RET tyrosine kinase domain becomes controlled by 5’ fused regulatory sequences of ubiquitously expressed genes that display coiled-coil regions with dimerization potential. Oncogenic activation of RET is apparently due to ligand-independent constitutive ectopic RET tyrosine kinase activity. The analysis of this cohort of children with radiation-induced thyroid tumors after Chernobyl provides insights into typical molecular aberrations in relation to a specific mode of environmental exposure and may serve as a paradigm for molecular genetic epidemiology.

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  1. Institute of Pathology, Ludwig Maximilians University, Thalkirchner Strasse 36, 80337, Munich, Germany

    H. M. Rabes & S. Klugbauer

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  1. H. M. Rabes
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  2. S. Klugbauer
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  1. Abteilung Zytogenetik, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, D-69120, Heidelberg, Germany

    Manfred Schwab

  2. Pathologisches Institut, Universität München, Thalkirchner Straße 36, D-80377, München, Germany

    Hartmut M. Rabes

  3. Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, D-69120, Heidelberg, Germany

    Klaus Munk

  4. Max-Planck-Institut für Biochemie, Am Klopferspitz 18a, D-82152, Martinsried, Germany

    Hans Peter Hofschneider

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Rabes, H.M., Klugbauer, S. (1998). Molecular Genetics of Childhood Papillary Thyroid Carcinomas After Irradiation: High Prevalence of RET Rearrangement. In: Schwab, M., Rabes, H.M., Munk, K., Hofschneider, H.P. (eds) Genes and Environment in Cancer. Recent Results in Cancer Research, vol 154. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-46870-4_16

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