{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T06:20:57Z","timestamp":1777875657240,"version":"3.51.4"},"reference-count":43,"publisher":"SAGE Publications","issue":"10","license":[{"start":{"date-parts":[[2019,10,1]],"date-time":"2019-10-01T00:00:00Z","timestamp":1569888000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Thyroid\u00ae"],"published-print":{"date-parts":[[2019,10]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>\n                      Inherited medullary thyroid carcinoma (MTC) is primarily caused by\n                      <jats:italic toggle=\"yes\">RET<\/jats:italic>\n                      mutations that are commonly localized in exons 5, 8, 10, 11, and 13\u201316. In this study, we report pedigrees for individuals with MTC that harbor a germline S409Y variant within exon 6 of the\n                      <jats:italic toggle=\"yes\">RET<\/jats:italic>\n                      proto-oncogene.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>\n                      Targeted sequencing was used to diagnose four apparently sporadic MTC index cases carrying the germline\n                      <jats:italic toggle=\"yes\">RET<\/jats:italic>\n                      S409Y (c.1226 C&gt;A) variant. Subsequently, 27 relatives of these individuals underwent clinical and genetic assessments and\/or thyroid surgery. Furthermore,\n                      <jats:italic toggle=\"yes\">in silico<\/jats:italic>\n                      analyses and\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      assays were performed to predict or verify the potential oncogenic activity of the S409Y variant.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      Overall, 15 of 31 participants were found to carry the\n                      <jats:italic toggle=\"yes\">RET<\/jats:italic>\n                      S409Y variant. Of these, 6 presented with isolated MTC (mean age 50.2 years; range 41\u201375 years), of which 3 presented with neck lymph node metastases and 2 presented with distant liver or lung metastases. Among the remaining 9 carriers, 3 (mean age 56 years; range 41\u201376 years) had elevated serum calcium-stimulated calcitonin (sCtn) or concurrent marginally elevated serum calcitonin (Ctn) levels, whereas the other 6 (mean age 37.5 years; range 14\u201352 years) exhibited typical Ctn\/sCtn levels (\n                      <jats:italic toggle=\"yes\">p<\/jats:italic>\n                      \u2009&lt;\u20090.05). None of the 15 carriers in these 4 families presented clinical evidence of pheochromocytoma, hyperparathyroidism, or Hirschsprung's disease.\n                      <jats:italic toggle=\"yes\">In silico<\/jats:italic>\n                      analyses revealed that S409Y was a \u201cpossibly damaging\u201d mutation that could affect the RET protein inter-domain interface. An\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      assay revealed that the phosphorylation level of RET tyrosine 905 was relatively higher in the\n                      <jats:italic toggle=\"yes\">RET<\/jats:italic>\n                      S409Y mutant than in wild-type (WT) RET. Moreover, transfection of HEK 293 cells with S409Y enhanced the phosphorylation activity of AKT, ERK pathways, and it increased cell proliferation compared with WT RET, but to a lesser degree than that for the\n                      <jats:italic toggle=\"yes\">RET<\/jats:italic>\n                      C618Y and C634Y mutations.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>\n                      This study demonstrates that the novel germline\n                      <jats:italic toggle=\"yes\">RET<\/jats:italic>\n                      S409Y variant is likely pathogenic and is associated with lower penetrance of MTC than that for the C618Y and C634Y mutations. Individuals with S409Y should be managed using a personalized approach, and additionally, \u201cat-risk\u201d family members should be evaluated. Additional studies are needed to elucidate the correlation between the S409Y mutation and multiple endocrine neoplasia type 2-specific tumors.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1089\/thy.2018.0385","type":"journal-article","created":{"date-parts":[[2019,7,31]],"date-time":"2019-07-31T05:24:21Z","timestamp":1564550661000},"page":"1447-1456","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":10,"title":["<i>RET<\/i>\n                    S409Y Germline Mutation and Associated Medullary Thyroid Carcinoma"],"prefix":"10.1177","volume":"29","author":[{"given":"Xiao-Ping","family":"Qi","sequence":"first","affiliation":[{"name":"Department of Oncologic and Urologic Surgery, The 903rd PLA Hospital, Wenzhou Medical University, Hangzhou, China."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bai-Ye","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Urology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peng-Fei","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Research and Development, XY Biotechnology Co. Ltd., Hangzhou, China."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sheng","family":"Wang","sequence":"additional","affiliation":[{"name":"Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology (KAUST), Jeddah, Saudi Arabia."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi-Hua","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Urologic Surgery, Yueqing People's Hospital, Wenzhou Medical University, Yueqing, China."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhi-Lie","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Oncologic and Urologic Surgery, The 903rd PLA Hospital, Wenzhou Medical University, Hangzhou, China."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiu-Hua","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Oncologic and Urologic Surgery, The 903rd PLA Hospital, Wenzhou Medical University, Hangzhou, China."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Oncologic and Urologic Surgery, The 903rd PLA Hospital, Wenzhou Medical University, Hangzhou, China."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xu-Dong","family":"Fang","sequence":"additional","affiliation":[{"name":"Department of Oncologic and Urologic Surgery, The 903rd PLA Hospital, Wenzhou Medical University, Hangzhou, China."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jian-Qiang","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Head and Neck Surgery, Zhejiang Cancer Hospital, Hangzhou, China."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"179","published-online":{"date-parts":[[2019,10,15]]},"reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2014.0335"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1159\/000346174"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2013-1204"},{"key":"e_1_3_4_5_2","unstructured":"The University of Utah Department of Pathology MEN 2 Database. 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