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dc.contributor.authorQi, Xiao-Ping
dc.contributor.authorJin, Bai-Ye
dc.contributor.authorLi, Peng-Fei
dc.contributor.authorWang, Sheng
dc.contributor.authorZhao, Yi-Hua
dc.contributor.authorCao, Zhi-Lie
dc.contributor.authorYu, Xiu-Hua
dc.contributor.authorCheng, Jun
dc.contributor.authorFang, Xu-Dong
dc.contributor.authorZhao, Jian-Qiang
dc.date.accessioned2019-08-08T13:07:49Z
dc.date.available2019-08-08T13:07:49Z
dc.date.issued2019-08-01
dc.identifier.citationQi, X.-P., Jin, B.-Y., Li, P.-F., Wang, S., Zhao, Y.-H., Cao, Z.-L., … Zhao, J.-Q. (2019). RET S409Y Germline Mutation and Associated Medullary Thyroid Carcinoma. Thyroid, 29(10), 1447–1456. doi:10.1089/thy.2018.0385
dc.identifier.doi10.1089/thy.2018.0385
dc.identifier.urihttp://hdl.handle.net/10754/656443
dc.description.abstractBACKGROUND:Inherited medullary thyroid cancinoma (MTC) is primarily caused by the RET mutation, commonly localised in exons 5, 8, 10, 11 and 13-16. We report herein four Chinese pedigrees with MTC harbouring a germline S409Y variant within exon 6 of RET proto-oncogene. METHODS:Using targeted sequencing, four apparently sporadic MTC index cases were diagnosed with the germline RET S409Y (c.1226 C>A) variant. Subsequently, their 27 relatives underwent clinical, genetic assessments and/or thyroid surgery. Furthermore, in silico analysis and in vitro assays were performed to predict or verify the potential oncogenic ability and protein structure of the S409Y variant. RESULTS:Overall, 15 of 31 participants were diagnosed with the RET S409Y variant; of these, 6 presented isolated MTC (mean age: 50.2 years; range: 41-75 years) with 3 presenting neck lymph node metastases, including 2 presenting distant liver or lung metastases. Among the remaining 9 carriers, 3 (mean age, 56 years; range, 41-76 years) reported elevated serum calcium-stimulated calcitonin (sCtn) or a concurrent marginally elevated serum calcitonin (Ctn) level; the remaining 6 (mean age, 37.5 years; range, 14-52 years) exhibited no abnormal Ctn/sCtn level (P < 0.05). None of all the 15 carriers presented clinical evidence for pheochromocytom or hyperparathyroidism in these four families. The in silico analysis revealed a 'possibly damaging' mutation for S409Y, resulting that could affect the organisation of the RET protein structural inter-domain interface; the in vitro assay revealed that phosphorylation level of the tyrosine 905 was a relatively stronger in the S409Y RET mutant, indicating ligand-independent autophosphorylation. Moreover, transfection with the S409Y induced an enhance effect of the transforming activity of PI3K/AKT, MAPK/ERK pathways and a greater aggressiveness ability of migration and invasion compared with wild-type RET, but all to a lesser degree than the C618Y and C634Y mutations. CONCLUSIONS:This study reveals that the novel germline RET S409Y variant is probably pathogenic and associated with lower penetrance of MTC. Nonetheless, individuals with S409Y should be managed using a personalized approach, and 'at-risk' additional families should be confirmed; the correlation between the S409Y mutation and MEN2-specific tumours should be further elucidated.
dc.relation.urlhttps://www.liebertpub.com/doi/10.1089/thy.2018.0385
dc.rightsArchived with thanks to Thyroid : official journal of the American Thyroid Association
dc.titleRET S409Y Germline Mutation and Associated Medullary Thyroid Carcinoma.
dc.typeArticle
dc.contributor.departmentComputer, Electrical and Mathematical Sciences and Engineering (CEMSE) Division
dc.identifier.journalThyroid : official journal of the American Thyroid Association
dc.rights.embargodate2020-08-01
dc.eprint.versionPost-print
dc.contributor.institutionDepartment of Oncologic and Urologic Surgery, the 903rd PLA Hospital, Wenzhou Medical University, Hangzhou, China
dc.contributor.institutionSchool of Medicine, Zhejiang University,, Department of Urology, The First Affiliated Hospital, Hangzhou, Zhejiang, China
dc.contributor.institutionY Biotechnology Co. Ltd, Hangzhou, Zhejiang, China
dc.contributor.institutionYueqing People's Hospital, Wenzhou Medical University, Department of Urologic Surgery, Yueqing, Zhejiang, China
dc.contributor.institutionZhejiang Cancer Hospital, Department of Head and Neck Surgery, Hangzhou, China
kaust.personWang, Sheng


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