{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T18:07:34Z","timestamp":1793729254225,"version":"4.6.1"},"reference-count":37,"publisher":"SAGE Publications","issue":"11","license":[{"start":{"date-parts":[[2025,11,1]],"date-time":"2025-11-01T00:00:00Z","timestamp":1761955200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"name":"the S\u00e3o Paulo State Research Foundation","award":["2021-02752-6"],"award-info":[{"award-number":["2021-02752-6"]}]},{"name":"the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences","award":["2023-PT320-05"],"award-info":[{"award-number":["2023-PT320-05"]}]},{"name":"the National Science Foundation of China","award":["82141115"],"award-info":[{"award-number":["82141115"]}]},{"name":"the National Science Foundation of China","award":["82370790"],"award-info":[{"award-number":["82370790"]}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Thyroid\u00ae"],"published-print":{"date-parts":[[2025,11,1]]},"abstract":"\n Background:<\/jats:title>\n \n The American Thyroid Association has stratified\n RET<\/jats:italic>\n C634 mutations as high risk. The association between\n RET<\/jats:italic>\n C634R mutation and a more aggressive medullary thyroid carcinoma (MTC) behavior compared with other C634 mutations remains inconclusive, possibly due to the lack of large cohorts and long-term outcome data. This study aimed to evaluate the aggressiveness and long-term outcomes of hereditary MTC in patients with different\n RET<\/jats:italic>\n codon 634 mutations.\n <\/jats:p>\n <\/jats:sec>\n \n Methods:<\/jats:title>\n \n This study is an international, multicenter, retrospective cohort study. Data from patients with hereditary MTC carrying\n RET<\/jats:italic>\n codon 634 mutations treated at three tertiary medical centers were retrospectively analyzed. Clinicopathological features and long-term outcomes were compared between patients with the C634R and those with other C634 mutations (C634F\/G\/S\/W\/Y).\n <\/jats:p>\n <\/jats:sec>\n \n Results:<\/jats:title>\n \n The study cohort included 317 patients (C634R: 133; C634F\/G\/S\/W\/Y: 184) from 137 families with a median follow-up of 10.6 years (4.9\u201316.6 years). Patients with the C634R mutation were slightly younger at the time of initial surgery (27.8\u2009\u00b1\u200912.1 vs. 31.3\u2009\u00b1\u200914.9,\n p<\/jats:italic>\n = 0.025). Meanwhile, the C634R group showed larger primary tumors (1.9\u2009\u00b1\u20091.2 vs. 1.5\u2009\u00b1\u20091.1,\n p<\/jats:italic>\n = 0.006). Kaplan\u2013Meier analysis revealed significantly higher cumulative rates and earlier occurrence of lymph node metastases (\n p<\/jats:italic>\n = 0.0003) and extrathyroidal extension (ETE;\n p<\/jats:italic>\n < 0.0001) in the C634R group. The C634R mutation was significantly associated with distant metastases (hazard ratio [HR]: 2.545 [confidence interval (CI) 1.134\u20135.713];\n p<\/jats:italic>\n = 0.024). Moreover, multivariable analysis identified\n RET<\/jats:italic>\n C634R genotype (HR: 6.488 [CI 1.364\u201330.862];\n p<\/jats:italic>\n = 0.019), increasing age (HR: 1.082 [CI 1.023\u20131.144];\n p<\/jats:italic>\n = 0.006), and ETE (HR: 9.695 [CI 2.344\u201340.105];\n p<\/jats:italic>\n = 0.002) to be significantly associated with worse disease-specific survival.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions:<\/jats:title>\n \n Prognosis varied in hereditary MTC patients with\n RET<\/jats:italic>\n C634 mutations. Our data highlight that the\n RET<\/jats:italic>\n C634R mutation was associated with greater tumor aggressiveness in MTC and a poorer disease-specific survival.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1177\/10507256251372196","type":"journal-article","created":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T18:52:36Z","timestamp":1759949556000},"page":"1259-1267","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":1,"title":["Do Prognostic Differences Exist Among High-Risk\n RET<\/i>\n Mutations? A Comparison of Outcomes Between the\n RET<\/i>\n C634R and Other C634 Mutations in Hereditary Medullary Thyroid Carcinoma"],"prefix":"10.1177","volume":"35","author":[{"given":"Jie","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2482-4675","authenticated-orcid":false,"given":"Luciana Audi","family":"Castroneves","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, S\u00e3o Paulo Cancer Institute (ICESP), S\u00e3o Paulo, Brazil."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan C.","family":"Lindsey","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Translational Endocrinology, Division of Endocrinology, Department of Medicine, Escola Paulista de Medicina, Universidade Federal de S\u00e3o Paulo, S\u00e3o Paulo, Brazil."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rulai","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyuan","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Ultrasound, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cleber P.","family":"Camacho","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Translational Endocrinology, Division of Endocrinology, Department of Medicine, Escola Paulista de Medicina, Universidade Federal de S\u00e3o Paulo, S\u00e3o Paulo, Brazil."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyan","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yulin","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiqi","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guang","family":"Ning","sequence":"additional","affiliation":[{"name":"Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiqing","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui M.B.","family":"Maciel","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Translational Endocrinology, Division of Endocrinology, Department of Medicine, Escola Paulista de Medicina, Universidade Federal de S\u00e3o Paulo, S\u00e3o Paulo, Brazil."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana O.","family":"Hoff","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, S\u00e3o Paulo Cancer Institute (ICESP), S\u00e3o Paulo, Brazil."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4064-4460","authenticated-orcid":false,"given":"Lei","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 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Biological properties of Ret with cysteine mutations correlate with multiple endocrine neoplasia type 2A, familial medullary thyroid carcinoma, and Hirschsprung\u2019s disease phenotype. 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(ed). AJCC Cancer Staging Manual. 8th ed.. Springer. 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