{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T12:19:39Z","timestamp":1791029979780,"version":"4.1.0"},"reference-count":13,"publisher":"The Endocrine Society","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2003,1,1]]},"abstract":"<jats:p>We have previously identified two second hit mechanisms involved in the development of multiple endocrine neoplasia type 2 (MEN 2)-associated tumors: trisomy 10 with duplication of the mutant RET allele and loss of the wild-type RET allele. However, some of the MEN 2-associated tumors investigated did not demonstrate either mechanism. Here, we studied the TT cell line derived from MEN 2-associated medullary thyroid carcinoma with a RET germline mutation in codon 634, for alternative mechanisms of tumorigenesis. Although we observed a 2:1 ratio between mutant and wild-type RET at the genomic DNA level in this cell line, fluorescence in situ hybridization analysis revealed neither trisomy 10 nor loss of the normal chromosome 10. Instead, a tandem duplication event was responsible for amplification of mutant RET. In further studies we could for the first time demonstrate that the genomic chromosome 10 abnormalities in this cell line cause an increased production of mutant RET mRNA. These findings provide evidence for a third second hit mechanism resulting in overrepresentation and overexpression of mutant RET in MEN 2-associated tumors.<\/jats:p>","DOI":"10.1210\/jc.2002-021254","type":"journal-article","created":{"date-parts":[[2003,1,8]],"date-time":"2003-01-08T12:42:41Z","timestamp":1042029761000},"page":"459-463","source":"Crossref","is-referenced-by-count":51,"title":["Amplification and Overexpression of Mutant RET in Multiple Endocrine Neoplasia Type 2-Associated Medullary Thyroid Carcinoma"],"prefix":"10.1210","volume":"88","author":[{"given":"Steve C.","family":"Huang","sequence":"first","affiliation":[{"name":"Molecular Pathogenesis Unit, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke (S.C.H., J.T.-C., S.D.P., A.O.V., P.M., I.A.L., Z.Z.), and Pediatric and Reproductive Endocrinology Branch, Maryland 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua","family":"Torres-Cruz","sequence":"additional","affiliation":[{"name":"Molecular Pathogenesis Unit, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke (S.C.H., J.T.-C., S.D.P., A.O.V., P.M., I.A.L., Z.Z.), and Pediatric and Reproductive Endocrinology Branch, Maryland 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Svetlana D.","family":"Pack","sequence":"additional","affiliation":[{"name":"Molecular Pathogenesis Unit, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke (S.C.H., J.T.-C., S.D.P., A.O.V., P.M., I.A.L., Z.Z.), and Pediatric and Reproductive Endocrinology Branch, Maryland 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian A.","family":"Koch","sequence":"additional","affiliation":[{"name":"National Institute of Child Health and Human Disease (C.A.K.), National Institutes of Health, Bethesda, Maryland 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander O.","family":"Vortmeyer","sequence":"additional","affiliation":[{"name":"Molecular Pathogenesis Unit, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke (S.C.H., J.T.-C., S.D.P., A.O.V., P.M., I.A.L., Z.Z.), and Pediatric and Reproductive Endocrinology Branch, Maryland 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Poonam","family":"Mannan","sequence":"additional","affiliation":[{"name":"Molecular Pathogenesis Unit, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke (S.C.H., J.T.-C., S.D.P., A.O.V., P.M., I.A.L., Z.Z.), and Pediatric and Reproductive Endocrinology Branch, Maryland 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina A.","family":"Lubensky","sequence":"additional","affiliation":[{"name":"Molecular Pathogenesis Unit, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke (S.C.H., J.T.-C., S.D.P., A.O.V., P.M., I.A.L., Z.Z.), and Pediatric and Reproductive Endocrinology Branch, Maryland 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert F.","family":"Gagel","sequence":"additional","affiliation":[{"name":"M. D. Anderson Cancer Center, University of Texas (R.F.G.), Houston, Texas 77030"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengping","family":"Zhuang","sequence":"additional","affiliation":[{"name":"Molecular Pathogenesis Unit, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke (S.C.H., J.T.-C., S.D.P., A.O.V., P.M., I.A.L., Z.Z.), and Pediatric and Reproductive Endocrinology Branch, Maryland 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","reference":[{"key":"2020071616565257900_R1","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1038\/ng0194-70","article-title":"Specific mutations of the RET proto-oncogene are related to disease phenotype in MEN 2A and FMTC.","volume":"6","author":"Mulligan","year":"1994","journal-title":"Nat Genet"},{"key":"2020071616565257900_R2","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1056\/NEJM199609263351307","article-title":"The RET proto-oncogene in multiple endocrine neoplasia type 2 and Hirschsprung\u2019s disease.","volume":"335","author":"Eng","year":"1996","journal-title":"N Engl J Med"},{"key":"2020071616565257900_R3","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1002\/path.1711720305","article-title":"Expression of the ret proto-oncogene product in human normal and neoplastic tissues of neural crest origin.","volume":"172","author":"Nakamura","year":"1994","journal-title":"J Pathol"},{"key":"2020071616565257900_R4","first-page":"1736","article-title":"The phenotypes associated with ret mutations in the multiple endocrine neoplasia type 2 syndrome.","volume":"59","author":"Ponder","year":"1999","journal-title":"Cancer Res"},{"key":"2020071616565257900_R5","first-page":"6223","article-title":"Duplication of the mutant RET allele in trisomy 10 or loss of the wild-type allele in multiple endocrine neoplasia type 2-associated pheochromocytomas.","volume":"60","author":"Huang","year":"2000","journal-title":"Cancer Res"},{"key":"2020071616565257900_R6","doi-asserted-by":"crossref","first-page":"7809","DOI":"10.1038\/sj.onc.1204991","article-title":"Allelic imbalance between the mutant and wild-type RET allele in MEN 2A-associated medullary thyroid carcinoma.","volume":"20","author":"Koch","year":"2001","journal-title":"Oncogene"},{"key":"2020071616565257900_R7","first-page":"95","article-title":"A new cell line for study of human medullary thyroid carcinoma","author":"Leong","year":"1981","journal-title":"In: Andreoli M, Monaco F, Robbins J, eds. Advances in thyroid neoplasia. Rome: Field Educational Italia;"},{"key":"2020071616565257900_R8","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/0165-4608(94)00185-E","article-title":"Cytogenetic characterization of three human and three rat medullary thyroid carcinoma cell lines.","volume":"80","author":"Cooley","year":"1995","journal-title":"Cancer Genet Cytogenet"},{"key":"2020071616565257900_R9","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1038\/1727","article-title":"Trisomy 7-harbouring non-random duplication of the mutant MET allele in hereditary papillary renal carcinomas.","volume":"20","author":"Zhuang","year":"1998","journal-title":"Nat Genet"},{"key":"2020071616565257900_R10","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1159\/000015485","article-title":"RET rearrangements in papillary thyroid carcinomas and adenomas detected by interphase FISH.","volume":"88","author":"Cinti","year":"2000","journal-title":"Cytogenet Cell Genet"},{"key":"2020071616565257900_R11","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1038\/25292","article-title":"Genetic instabilities in human cancers.","volume":"396","author":"Lengauer","year":"1998","journal-title":"Nature"},{"key":"2020071616565257900_R12","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1038\/ng721","article-title":"Wildtype kras2 can inhibit lung carcinogenesis in mice.","volume":"29","author":"Zhang","year":"2001","journal-title":"Nat Genet"},{"key":"2020071616565257900_R13","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1038\/ng0901-3","article-title":"A new verdict for an old convict.","volume":"29","author":"Pfeifer","year":"2001","journal-title":"Nat Genet"}],"container-title":["The Journal of Clinical Endocrinology &amp; Metabolism"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/jcem\/article-pdf\/88\/1\/459\/10744323\/jcem0459.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/jcem\/article-pdf\/88\/1\/459\/10744323\/jcem0459.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,7,16]],"date-time":"2020-07-16T23:28:11Z","timestamp":1594942091000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jcem\/article\/88\/1\/459\/2846098"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2003,1,1]]},"references-count":13,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2003,1,1]]}},"URL":"https:\/\/doi.org\/10.1210\/jc.2002-021254","relation":{},"ISSN":["0021-972X","1945-7197"],"issn-type":[{"value":"0021-972X","type":"print"},{"value":"1945-7197","type":"electronic"}],"subject":[],"published":{"date-parts":[[2003,1,1]]}}}