{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T07:51:11Z","timestamp":1776153071658,"version":"3.50.1"},"reference-count":24,"publisher":"Oxford University Press (OUP)","issue":"5","content-domain":{"domain":["eje.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2014,11]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Rearranged during transfection (<jats:italic>RET<\/jats:italic>) mutations are well-known genetic events in sporadic and familial medullary thyroid carcinoma (FMTC). The presence of<jats:italic>RAS<\/jats:italic>mutations in sporadic cases, challenging the<jats:italic>RET<\/jats:italic>paradigm in these tumors, has been recently reported. We intend to evaluate mTOR pathway activation in<jats:italic>RET<\/jats:italic>- and<jats:italic>RAS<\/jats:italic>-mutated MTC.<\/jats:p><\/jats:sec><jats:sec><jats:title>Materials and methods<\/jats:title><jats:p>In this study, we analysed the presence of<jats:italic>RET, H-RAS<\/jats:italic>, and<jats:italic>K-RAS<\/jats:italic>mutations in a series of 87 MTCs (82 apparently sporadic and five FMTCs; five apparently sporadic MTCs were eventually found to be familial). We also evaluated mTOR activation \u2013 using the expression of its downstream effector phospho-S6 ribosomal protein (p-S6) and the expression of the mTOR inhibitor, phosphatase and tensin homologue deleted on chromosome 10 (PTEN) \u2013 by immunohistochemistry.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Our results revealed that<jats:italic>RET<\/jats:italic>mutations were present in 52.9% of the cases (46\/87) and<jats:italic>RAS<\/jats:italic>mutations in 12.6% (11\/87) of the whole series of MTCs and 14.3% of the 77 sporadic MTCs. The presence of<jats:italic>RET<\/jats:italic>and<jats:italic>RAS<\/jats:italic>mutations was mutually exclusive.<jats:italic>RAS<\/jats:italic>mutations were significantly associated with higher intensity of p-S6 expression (<jats:italic>P<\/jats:italic>=0.007), suggesting that the mTOR pathway is activated in such MTCs. We observed also an increased expression of p-S6 in invasive tumors (<jats:italic>P<\/jats:italic>=0.042) and in MTCs with lymph node metastases (<jats:italic>P<\/jats:italic>=0.046). Cytoplasmic<jats:italic>PTEN<\/jats:italic>expression was detected in 58.8% of the cases; cases WT for<jats:italic>RAS<\/jats:italic>showed a significantly lower expression of<jats:italic>PTEN<\/jats:italic>(<jats:italic>P<\/jats:italic>=0.045).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>We confirmed the presence of<jats:italic>RAS<\/jats:italic>mutation in 14.3% of sporadic MTCs and report, for the first time, an association between such mutations and the activation of the mTOR pathway. The evaluation of the mTOR activation by pS6 expression may serve as an indicator of invasive MTC.<\/jats:p><\/jats:sec>","DOI":"10.1530\/eje-14-0389","type":"journal-article","created":{"date-parts":[[2014,8,28]],"date-time":"2014-08-28T03:14:07Z","timestamp":1409195647000},"page":"633-640","update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-1","source":"Crossref","is-referenced-by-count":32,"title":["mTOR activation in medullary thyroid carcinoma with RAS mutation"],"prefix":"10.1093","volume":"171","author":[{"given":"Joana","family":"Lyra","sequence":"first","affiliation":[]},{"given":"Jo\u00e3o","family":"Vinagre","sequence":"additional","affiliation":[]},{"given":"Rui","family":"Batista","sequence":"additional","affiliation":[]},{"given":"Vasco","family":"Pinto","sequence":"additional","affiliation":[]},{"given":"Hugo","family":"Prazeres","sequence":"additional","affiliation":[]},{"given":"Fernando","family":"Rodrigues","sequence":"additional","affiliation":[]},{"given":"Catarina","family":"Eloy","sequence":"additional","affiliation":[]},{"given":"Manuel","family":"Sobrinho-Sim\u00f5es","sequence":"additional","affiliation":[]},{"given":"Paula","family":"Soares","sequence":"additional","affiliation":[]}],"member":"286","reference":[{"key":"1_48788011","doi-asserted-by":"crossref","first-page":"1S","DOI":"10.1186\/1756-6614-6-S1-S1","volume":"6","year":"2013","journal-title":"THYROID RESEARCH"},{"key":"2_34113245","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1038\/ncpendmet0717","volume":"4","year":"2008","journal-title":"NATURE CLINICAL PRACTICE ENDOCRINOLOGY METABOLISM"},{"issue":"1-2","key":"3_35737004","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1016\/j.mce.2009.09.027","volume":"315","author":"Grozinsky-Glasberg","year":"2010","journal-title":"Molecular and cellular endocrinology","ISSN":"https:\/\/id.crossref.org\/issn\/0303-7207","issn-type":"print"},{"key":"4_48788012","first-page":"678357","volume":"2011","year":"2011","journal-title":"JOURNAL OF THYROID RESEARCH"},{"issue":"10","key":"5_43916691","doi-asserted-by":"publisher","first-page":"e46869","DOI":"10.1371\/journal.pone.0046869","volume":"7","author":"Couto","year":"2012","ISSN":"https:\/\/id.crossref.org\/issn\/1932-6203","issn-type":"print"},{"issue":"3","key":"6_41960515","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1097\/CCO.0b013e328351c71a","volume":"24","author":"Almeida","year":"2012","journal-title":"Current opinion in oncology","ISSN":"https:\/\/id.crossref.org\/issn\/1040-8746","issn-type":"print"},{"issue":"6","key":"7_22168533","doi-asserted-by":"publisher","first-page":"659","DOI":"10.1111\/j.1365-2265.2006.02524.x","volume":"64","author":"Prazeres","year":"2006","journal-title":"Clinical endocrinology","ISSN":"https:\/\/id.crossref.org\/issn\/0300-0664","issn-type":"print"},{"key":"8_48788013","first-page":"1","volume":"12","year":"2013","journal-title":"CURRENT GENOMICS"},{"issue":"3","key":"9_30049324","doi-asserted-by":"publisher","first-page":"682","DOI":"10.1210\/jc.2007-1714","volume":"93","year":"2008","journal-title":"Journal of Clinical Endocrinology &amp; 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