Michiels F M, Billaud M
Laboratoire de Génétique Oncologique, UMR 1599 CNRS, Institut Gustave Roussy, Villejuif, France.
Arch Anat Cytol Pathol. 1998;46(1-2):19-30.
The RET proto-oncogene encodes a receptor tyrosine kinase which plays a crucial role during the embryonic development of the enteric nervous system and of the kidney. Cytogenetic analyses of papillary thyroid carcinoma (PTC), a neoplasm which originates from thyrocytes, have revealed that somatic rearrangements of the RET gene are involved in the etiology of a significant proportion of this tumour. Medullary thyroid carcinoma (MTC) which arises from neural-crest derived C-cells is the cardinal disease feature of multiple endocrine neoplasia type 2 (MEN 2), a dominantly inherited cancer syndrome. Recent studies have provided evidence that germline mutations of the RET gene are the underlying genetic events responsible for MEN 2. This review focuses on the role of RET mutations in the pathogenesis of PTC and MTC and summarizes our present knowledge on the consequences of these alterations on the RET tyrosine kinase function. We further describe a transgenic mouse model for hereditary MTC. Mice carrying a MEN 2A allele of RET under the control of the CGRP/calcitonin promoter develop bilateral and multifocal MTC, morphologically and biologically similar to human MTC.
RET原癌基因编码一种受体酪氨酸激酶，其在肠神经系统和肾脏的胚胎发育过程中起着至关重要的作用。甲状腺乳头状癌（PTC）起源于甲状腺细胞，对其进行的细胞遗传学分析显示，RET基因的体细胞重排参与了该肿瘤相当一部分的病因学过程。起源于神经嵴衍生的C细胞的甲状腺髓样癌（MTC）是2型多发性内分泌肿瘤（MEN 2）的主要疾病特征，MEN 2是一种显性遗传的癌症综合征。最近的研究提供了证据表明，RET基因的种系突变是导致MEN 2的潜在遗传事件。本综述重点关注RET突变在PTC和MTC发病机制中的作用，并总结我们目前对这些改变对RET酪氨酸激酶功能影响的认识。我们进一步描述了一种遗传性MTC的转基因小鼠模型。在降钙素基因相关肽/降钙素启动子控制下携带RET的MEN 2A等位基因的小鼠会发生双侧和多灶性MTC，其形态和生物学特征与人类MTC相似。
