{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T21:09:45Z","timestamp":1774645785133,"version":"3.50.1"},"reference-count":17,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2015,12,15]],"date-time":"2015-12-15T00:00:00Z","timestamp":1450137600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical Endocrinology"],"published-print":{"date-parts":[[2016,2]]},"abstract":"Summary<\/jats:title>Objective<\/jats:title>Controversy surrounds the importance of the different amino acids substituting for cysteine in RE<\/jats:styled-content>arranged during Transfection (RET<\/jats:styled-content>) codon 634 for multiple endocrine neoplasia 2A (MEN<\/jats:styled-content> 2A). This study aimed to clarify the relevance of these amino acid substitutions for the development of MEN<\/jats:styled-content> 2A.<\/jats:p><\/jats:sec>Design<\/jats:title>Cross\u2010sectional study at surgical referral centres in Germany.<\/jats:p><\/jats:sec>Patients<\/jats:title>Included were 184 carriers of RET<\/jats:styled-content><\/jats:italic> mutations in codon 634.<\/jats:p><\/jats:sec>Measurements<\/jats:title>Arginine (79 carriers) and tyrosine (50 carriers) substitutions in codon 634 were compared with each other and, for the first time, gauged against a common reference standard comprising all other amino acid substitutions (phenylalanine, 35 carriers; serine, 12 carriers; glycine, 7 carriers; tryptophan, 1 carrier).<\/jats:p><\/jats:sec>Results<\/jats:title>Arginine substitutions in codon 634 were associated with higher penetrance of medullary thyroid cancer (MTC<\/jats:styled-content>; 82% vs<\/jats:italic> 62%; P\u00a0<\/jats:italic>=\u00a0<\/jats:italic>0\u00b7010), any phaeochromocytoma (44% vs<\/jats:italic> 15%, P\u00a0<\/jats:italic><\u00a0<\/jats:italic>0\u00b7001), bilateral phaeochromocytoma (32% vs<\/jats:italic> 5%; P\u00a0<\/jats:italic><\u00a0<\/jats:italic>0\u00b7001) and primary hyperparathyroidism (18% vs<\/jats:italic> 5%; P\u00a0<\/jats:italic>=\u00a0<\/jats:italic>0\u00b7039) relative to the reference standard. The penetrance rates of any phaeochromocytoma (44% vs<\/jats:italic> 26%; P\u00a0<\/jats:italic>=\u00a0<\/jats:italic>0\u00b7041) and bilateral phaeochromocytoma (32% vs<\/jats:italic> 14%; P\u00a0<\/jats:italic>=\u00a0<\/jats:italic>0\u00b7035) were also higher with arginine than with tyrosine substitutions. Corrected for multiple testing, the associations of arginine with any phaeochromocytoma and bilateral phaeochromocytoma remained statistically significant. Progression of MTC<\/jats:styled-content>, evidenced by largest primary tumour diameter, nodal status, distant metastasis and biochemical cure, did not differ by amino acid substitution.<\/jats:p><\/jats:sec>Conclusions<\/jats:title>In codon 634, arginine substitutions for cysteine may cause slightly higher penetrance rates of MEN<\/jats:styled-content> 2A which, overall, are too small to treat carriers differently. The mode of action by which arginine exerts these subtle effects warrants further research.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cen.12978","type":"journal-article","created":{"date-parts":[[2015,11,17]],"date-time":"2015-11-17T09:32:52Z","timestamp":1447752772000},"page":"210-215","source":"Crossref","is-referenced-by-count":13,"title":["Variability in penetrance of multiple endocrine neoplasia 2A with amino acid substitutions in RET codon 634"],"prefix":"10.1111","volume":"84","author":[{"given":"Andreas","family":"Machens","sequence":"first","affiliation":[{"name":"Department of General, Visceral and Vascular Surgery Martin\u2010Luther\u2010University Halle\u2010Wittenberg Halle (Saale) Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henning","family":"Dralle","sequence":"additional","affiliation":[{"name":"Department of General, Visceral and Vascular Surgery Martin\u2010Luther\u2010University Halle\u2010Wittenberg Halle (Saale) Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2015,12,15]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1136\/jcp.18.3.288"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/2.7.851"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/363458a0"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3680"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.15.3.1613"},{"key":"e_1_2_8_7_1","first-page":"2870","article-title":"Biological properties of Ret with cysteine mutations correlate with multiple endocrine neoplasia type 2A, familial medullary thyroid carcinoma, and Hirschsprung's disease phenotype","volume":"57","author":"Ito S.","year":"1997","journal-title":"Cancer Research"},{"key":"e_1_2_8_8_1","doi-asserted-by":"crossref","first-page":"1575","DOI":"10.1001\/jama.1996.03540190047028","article-title":"The relationship between specific RET proto\u2010oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. 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Le Groupe d'Etude des Tumeurs \u00e0 Calcitonine","volume":"60","author":"Schuffenecker I.","year":"1997","journal-title":"American Journal of Human Genetics"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-14-0818"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa012915"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2002-021422"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2015-1689"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1097\/SLA.0b013e3181ae333f"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-12-0919"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djh075"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMp078120"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2012-3192"}],"container-title":["Clinical Endocrinology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fcen.12978","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cen.12978","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,24]],"date-time":"2023-09-24T06:16:44Z","timestamp":1695536204000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cen.12978"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,12,15]]},"references-count":17,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2016,2]]}},"alternative-id":["10.1111\/cen.12978"],"URL":"https:\/\/doi.org\/10.1111\/cen.12978","archive":["Portico"],"relation":{},"ISSN":["0300-0664","1365-2265"],"issn-type":[{"value":"0300-0664","type":"print"},{"value":"1365-2265","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,12,15]]}}}