The TRK-T1 fusion protein induces neoplastic transformation of thyroid epithelium

Genetic analysis of human papillary thyroid carcinomas (PTC) has revealed unique chromosomal translocations that form oncogenic fusion proteins and promote thyroid tumorigenesis in up to 60% of tumors examined. Although, the majority of thyroid specific translocations involve the growth factor receptor c-RET, variant rearrangements of the receptor for nerve growth factor, NTRK1 have also been described. One such translocation, TRK-T1, forms a fusion protein composed of the carboxyl terminal tyrosine kinase domain of NTRK1 and the amino terminal portion of TPR (Translocated Promoter Region). To determine if TRK-T1 expression can cause thyroid cancer in vivo, we developed transgenic mice that express the human TRK-T1 fusion protein in the thyroid. Immunohistochemical analysis of TRK-T1 transgenic mouse thyroids revealed TRK-T1 staining within the thyroid follicular epithelium. In contrast to nontransgenic littermates, 54% of transgenic mice developed thyroid abnormalities that included follicular hyperplasia and papillary carcinoma. Furthermore, all transgenic mice examined greater than 7 months of age developed thyroid hyperplasia and/or carcinoma. These data support the conclusion that TRK-T1 is oncogenic in vivo and contributes to the neoplastic transformation of the thyroid.

[1]  M. Pierotti,et al.  Role of the TFG N-terminus and coiled-coil domain in the transforming activity of the thyroid TRK-T3 oncogene , 1998, Oncogene.

[2]  J. Jardillier,et al.  Ret and trk proto-oncogene activation in thyroid papillary carcinomas in French patients from the Champagne-Ardenne region. , 1996, Clinical biochemistry.

[3]  P. Dobrowolski.  Short protocols in molecular biology. 2nd ed. A compendium of methods from “current protocols in molecular biology”. edited by FREDERICK M. AUSUBELet al., John Wiley & Sons, 1992., ISBN 0‐471‐57735‐9 , 1993 .

[4]  H. Rabes,et al.  NTRK1 re‐arrangement in papillary thyroid carcinomas of children after the Chernobyl reactor accident , 1999, International journal of cancer.

[5]  M. Borrello,et al.  Cytogenetics and molecular genetics of carcinomas arising from thyroid epithelial follicular cells , 1996, Genes, chromosomes & cancer.

[6]  H. Rabes,et al.  Molecular genetics of childhood papillary thyroid carcinomas after irradiation: high prevalence of RET rearrangement. , 1998, Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer.

[7]  B. Ponder,et al.  Full activation of MEN2B mutant RET by an additional MEN2A mutation or by ligand GDNF stimulation , 1998, Oncogene.

[8]  B. Hogan,et al.  Manipulating the mouse embryo: A laboratory manual , 1986 .

[9]  M. Barbacid,et al.  A human oncogene formed by the fusion of truncated tropomyosin and protein tyrosine kinase sequences , 1986, Nature.

[10]  Masahide Takahashi,et al.  Low Frequency of Rearrangements of the ret and trk Proto‐oncogenes in Japanese Thyroid Papillary Carcinomas , 1992, Japanese journal of cancer research : Gann.

[11]  A. Lupas,et al.  The DNA rearrangement that generates the TRK-T3 oncogene involves a novel gene on chromosome 3 whose product has a potential coiled-coil domain , 1995, Molecular and cellular biology.

[12]  M. Santoro,et al.  Human N-ras, TRK-T1, and RET/PTC3 oncogenes, driven by a thyroglobulin promoter, differently affect the expression of differentiation markers and the proliferation of thyroid epithelial cells. , 1999, Oncology research.

[13]  G. G. Stokes.  "J." , 1890, The New Yale Book of Quotations.

[14]  M. Pierotti,et al.  Cytogenetic and molecular genetic characterization of papillary thyroid carcinomas , 1992, Genes, chromosomes & cancer.

[15]  L. Mariani,et al.  Age-related activation of the tyrosine kinase receptor protooncogenes RET and NTRK1 in papillary thyroid carcinoma. , 1996, The Journal of clinical endocrinology and metabolism.

[16]  D. Wynford‐Thomas,et al.  Origin and progression of thyroid epithelial tumours: cellular and molecular mechanisms. , 1997, Hormone research.

[17]  A. Fusco,et al.  One- and two-step transformations of rat thyroid epithelial cells by retroviral oncogenes , 1987, Molecular and cellular biology.

[18]  J. Sagartz,et al.  Thyroid-stimulating hormone promotes growth of thyroid carcinomas in transgenic mice with targeted expression of the ret/PTC1 oncogene. , 1997, Laboratory investigation; a journal of technical methods and pathology.

[19]  J. Sagartz,et al.  Targeted expression of the ret/PTC1 oncogene induces papillary thyroid carcinomas. , 1996, Endocrinology.