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Mutation Analysis Reveals Novel Sequence Variants in NTRK1 in Sporadic Human Medullary Thyroid Carcinoma¹

Clinical Cancer Genetics and Human Cancer Genetics Programs (O.G., C.E.), Comprehensive Cancer Center, Ohio State University, Columbus, Ohio 43210; Division of Experimental Oncology A (A.G., M.A.P.), Istituto Nazionale Tumori, Via G. Venetion, 20133 Milan, Italy; Department of General Surgery (C.H.-V., H.D.), Martin Luther University of Halle-Wittenberg, 06097 Halle/Saale, Germany; Cancer Research Campaign Human Cancer Genetics Research Group (C.E.), University of Cambridge, Cambridge CB2 2QQ, United Kingdom

Address all correspondence and requests for reprints to: Charis Eng, M.D., Ph.D., Human Cancer Genetics Program, Comprehensive Cancer Center, Ohio State University, 420 West 12th Avenue, Room 690C MRF, Columbus, Ohio 43210. E-mail: eng-1{at}medctr.osu.edu

Tyrosine kinase NTRK1 is expressed in neural and nonneuronal tissues. Like RET, NTRK1 is often activated by rearrangements that involve one of at least five other genes in papillary thyroid carcinoma (PTC). Because of similarities in involvement of the two tyrosine kinases RET (rearranged during transfection) and NTRK1 in the pathogenesis of PTC, the obvious parallels between RET and NTRK1 and between PTC and medullary thyroid carcinoma (MTC), NTRK1 seemed to be an excellent candidate gene to play a role in the genesis of MTC. Single-strand conformational polymorphism analysis of 16 exons of NTRK1, from 31 sporadic MTC, revealed variants in five exons (exons 4 and 14–17). Sequence analysis demonstrated one sequence variant each in exons 4, 14, 16, and 17, and four different variants in exon 15. Differential restriction enzyme digestion specific for each variant confirmed the sequencing results. All variants were also present in the corresponding germline DNA. Interestingly, the sequence variants at codon 604 (c1810C>T) and codon 613 (c1838G>T) of exon 15 always occurred together and might represent linkage disequilibrium. The frequencies of the sequence variants in germline DNA from patients with sporadic MTC did not differ significantly from those in a race-matched control group. Although we did not find any somatic mutations of NTRK1 in sporadic MTC, the single-strand conformational polymorphism conditions reported here, together with the knowledge of the frequency of various sequence variants, may help in future mutation analyses of DNA from other neural and nonneural tissues.

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