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Heterogeneity in the Distribution of RET/PTC Rearrangements within Individual Post-Chernobyl Papillary Thyroid Carcinomas

Institutes of Molecular Radiobiology (K.U., H.Z., H.B., P.K.) and Pathology (P.H., G.T.), GSF-National Research Center for Environment and Health, D-85764 Neuherberg, Germany; Department of Cellular and Molecular Pathology/Instituto di Endocrinologia ed Oncologia Sperimentale Consiglio Nazionale delle Ricerche Universita di Napoli Federico II, 80131 Naples, Italy (G.S., M.S.); Institute of Endocrinology and Metabolism (T.B., L.Z., N.T.), Academy of Medical Sciences of the Ukraine, 254114 Kiev, Ukraine; and South West Wales Cancer Institute, Singleton Hospital, SA2 8QA Swansea, United Kingdom (P.H., G.T.)

Address all correspondence and requests for reprints to: Dr. Horst Zitzelsberger, GSF-Forschungszentrum für Umwelt und Gesundheit GmbH, Institute of Molecular Radiobiology, Ingolstädter Landstrasse 1, D-85764 Neuherberg, Germany. E-mail: Zitzelsberger{at}gsf.de.

The nuclear disaster that occurred in Chernobyl in 1986 offered the unique opportunity to study the molecular genetics of one human tumor type, papillary carcinoma of the thyroid gland, associated with a specific etiology. We have analyzed RET rearrangements in post-Chernobyl papillary thyroid carcinomas (n = 29), follicular thyroid adenomas (n = 2), and follicular thyroid carcinoma (n = 1) by interphase fluorescence in situ hybridization (FISH) analysis on paraffin-embedded tissue sections. Paraffin sections were microdissected before use to ensure that only tumor was present. Cell nuclei were scored for the presence of a split FISH signal (separated red and green signal) in addition to an overlapping signal. Only cells with either two overlapping signals or one split and one overlapping signal were counted to ensure that only complete cell nuclei had been scored. In total, 23 of 32 cases (72%) showed RET rearrangements diagnosed by FISH interphase analysis. In all cases, the tumors were composed of a mixture of cells with and without ret rearrangement on FISH. In some cases, this distribution was clearly nonrandom because clustering of rearranged cells was detected within the same tumor nodule. Accordingly, only 31% of the cases positive for rearrangement on FISH also scored positive using RT-PCR. These findings suggest that because RET/PTC rearrangements are not present in a majority of tumor cells, either a fraction of post-Chernobyl papillary thyroid tumors are of multiclonal origin, or ret rearrangement is a later, subclonal event.

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