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Proximity of TPR and NTRK1 Rearranging Loci in Human Thyrocytes

¹ Department of Experimental Oncology Operative Unit "Molecular Mechanisms of Cancer Growth and Progression," Istituto Nazionale Tumori; ² Department of Human Morphology, University of Milan; and ³ The FIRC Institute of Molecular Oncology Foundation, Milan, Italy

Requests for reprints: Angela Greco or Marco A. Pierotti, Department of Experimental Oncology Operative Unit "Molecular Mechanisms of Cancer Growth and Progression," Istituto Nazionale Tumori, Via Venezian 1, 20133 Milan, Italy. Phone: 39-223903222; Fax: 39-223902764; E-mail: angela.greco{at}istitutotumori.mi.it or marco.pierotti{at}istitutotumori.mi.it.

Chromosomal rearrangements are frequently associated with cancer; the mechanisms underlying their cell-type specificity are poorly understood. Papillary thyroid carcinomas are marked by a high frequency of chromosome rearrangements involving the RET and NTRK1 tyrosine kinase receptor genes and producing RET and TRK oncogenes. An explanation for the propensity of thyrocytes to undergo gene rearrangements has been recently proposed by Nikiforova and colleagues, who showed that the recombination between RET and H4 is favored by the loci proximity in interphase nuclei. We investigated whether the spatial proximity is a contributing factor also in the generation of the thyroid-specific TRK oncogenes. The distance between NTRK1 and its oncogenic partner TPR was determined by two-color fluorescence in situ hybridization and two-dimensional microscopy. A three-dimensional reconstruction of the data was also done. We show that the two loci in thyrocytes nuclei display a distance reduced with respect to peripheral blood lymphocytes, thus supporting the notion that spatial proximity of translocation-prone gene loci may favor gene rearrangements.

Key Words: chromosomal rearrangements • TRK oncogenes • loci proximity • NTRK1 • TPR

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