{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:31:51Z","timestamp":1760059911604,"version":"build-2065373602"},"reference-count":24,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,7,18]],"date-time":"2025-07-18T00:00:00Z","timestamp":1752796800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CIMB"],"abstract":"<jats:p>Background: Medullary thyroid carcinoma (MTC) has a high rate of local and distant metastases. In particular, the RET protooncogene appears to be the predominant driver mutation for oncogenesis. The German S3 thyroid carcinoma guidelines recommend molecular genetic analysis of the tumour without specifying the site of the tissue sampling. Whether there is difference in RET protooncogene between the primary tumour, lymph node, and distant metastasis has not yet been investigated. However, differences could be important with regard to biopsy localization, and also, thus, the choice of single- or multi-tyrosine-kinase-inhibitor therapy. Methods: In a case of sporadic MTC, Cancer Hotspot panel diagnostics were performed on the primary tumour, lymph node metastasis, and distant metastasis. Mutations were classified using different gene databases, and the different stages of metastasis were compared. Results: RET protooncogene (chr10:43609933, c.1886_1891delTGTGCG, p.Leu629_Asp631delinsHis) was found to be present in the MTC tissue of the primary tumour, lymph node, and distant metastasis in the Cancer Hotspot Panel diagnostic, while the other investigated therapy-relevant mutational profiles were not consistently found. Conclusions: Further longitudinal studies in larger patient cohorts are required to elucidate the role of the RET protooncogene in the metastatic progression of MTC and to determine its impact on the selection of biopsy sites and the subsequent decision-making regarding single- versus multi-tyrosine kinase inhibitor therapy.<\/jats:p>","DOI":"10.3390\/cimb47070560","type":"journal-article","created":{"date-parts":[[2025,7,18]],"date-time":"2025-07-18T11:12:34Z","timestamp":1752837154000},"page":"560","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Next-Generation Sequencing Reveals the Potential Role of RET Protooncogene in Metastasis Progression in Medullary Thyroid Cancer"],"prefix":"10.3390","volume":"47","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0569-645X","authenticated-orcid":false,"given":"Maurice","family":"Klein","sequence":"first","affiliation":[{"name":"Department of Oral & Maxillofacial Surgery, School of Medicine, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna Julia Claudia","family":"Klein","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology and Head and Neck Surgery, School of Medicine, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arnold M.","family":"Raem","sequence":"additional","affiliation":[{"name":"Arrows Biomedical Deutschland GmbH, CeNTech Heisenbergstra\u00dfe 11, 48149 M\u00fcnster, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicklas","family":"Garrelfs","sequence":"additional","affiliation":[{"name":"Department of Intensive and Intermediate Care, Pauwelsstrasse 30, 52074 Aachen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henrike J.","family":"Fischer","sequence":"additional","affiliation":[{"name":"Institute of Immunology, Medical Faculty, RWTH Aachen University, Pauwelsstr. 30, 52074 Aachen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frank","family":"H\u00f6lzle","sequence":"additional","affiliation":[{"name":"Department of Oral & Maxillofacial Surgery, School of Medicine, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kai","family":"Wermker","sequence":"additional","affiliation":[{"name":"Department of Oral and Cranio-Maxillofacial Surgery, Klinikum Osnabr\u00fcck GmbH, Am Finkenh\u00fcgel 1, 49076 Osnabr\u00fcck, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2783","DOI":"10.1016\/S0140-6736(16)30172-6","article-title":"Thyroid Cancer","volume":"388","author":"Cabanillas","year":"2016","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"103957","DOI":"10.1016\/j.critrevonc.2023.103957","article-title":"NTRK Fusions in Thyroid Cancer: Pathology and Clinical Aspects","volume":"184","author":"Ma","year":"2023","journal-title":"Crit. Rev. Oncol.\/Hematol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1530\/EJE-11-1060","article-title":"Additive Effect of RET Polymorphisms on Sporadic Medullary Thyroid Carcinoma Susceptibility and Tumor Aggressiveness","volume":"166","author":"Ceolin","year":"2012","journal-title":"Eur. J. Endocrinol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1046\/j.1365-2265.1998.00392.x","article-title":"Prognostic Factors for Survival and for Biochemical Cure in Medullary Thyroid Carcinoma: Results in 899 Patients","volume":"48","author":"Modigliani","year":"1998","journal-title":"Clin. Endocrinol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Khatami, F., and Tavangar, S.M. (2018). Multiple Endocrine Neoplasia Syndromes from Genetic and Epigenetic Perspectives. Biomark Insights, 13.","DOI":"10.1177\/1177271918785129"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1111\/j.1365-2265.2004.02037.x","article-title":"Medullary Thyroid Carcinoma","volume":"61","author":"Leboulleux","year":"2004","journal-title":"Clin. Endocrinol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2070","DOI":"10.1210\/jc.2002-021713","article-title":"Rationale for Central and Bilateral Lymph Node Dissection in Sporadic and Hereditary Medullary Thyroid Cancer","volume":"88","author":"Scollo","year":"2003","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1960","DOI":"10.1007\/s00268-007-9185-1","article-title":"Increased Risk of Lymph Node Metastasis in Multifocal Hereditary and Sporadic Medullary Thyroid Cancer","volume":"31","author":"Machens","year":"2007","journal-title":"World J. Surg."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"E364","DOI":"10.1210\/jc.2012-2703","article-title":"Exomic Sequencing of Medullary Thyroid Cancer Reveals Dominant and Mutually Exclusive Oncogenic Mutations in RET and RAS","volume":"98","author":"Agrawal","year":"2013","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3639","DOI":"10.1200\/JCO.2012.48.4659","article-title":"Cabozantinib in Progressive Medullary Thyroid Cancer","volume":"31","author":"Elisei","year":"2013","journal-title":"J. Clin. Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1200\/JCO.2011.35.5040","article-title":"Vandetanib in Patients with Locally Advanced or Metastatic Medullary Thyroid Cancer: A Randomized, Double-Blind Phase III Trial","volume":"30","author":"Wells","year":"2012","journal-title":"J. Clin. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1007\/978-3-319-91442-8_5","article-title":"Cabozantinib: Multi-Kinase Inhibitor of MET, AXL, RET, and VEGFR2","volume":"Volume 211","author":"Martens","year":"2018","journal-title":"Small Molecules in Oncology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1056\/NEJMoa2005651","article-title":"Efficacy of Selpercatinib in RET-Altered Thyroid Cancers","volume":"383","author":"Wirth","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1851","DOI":"10.1056\/NEJMoa2309719","article-title":"Phase 3 Trial of Selpercatinib in Advanced RET-Mutant Medullary Thyroid Cancer","volume":"389","author":"Hadoux","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/j.beem.2017.04.009","article-title":"Chemotherapy and Tyrosine-Kinase Inhibitors for Medullary Thyroid Cancer","volume":"31","author":"Hadoux","year":"2017","journal-title":"Best Pract. Res. Clin. Endocrinol. Metab."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3812","DOI":"10.1093\/nar\/gkg509","article-title":"SIFT: Predicting Amino Acid Changes That Affect Protein Function","volume":"31","author":"Ng","year":"2003","journal-title":"Nucleic Acids Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1038\/nmeth0410-248","article-title":"A Method and Server for Predicting Damaging Missense Mutations","volume":"7","author":"Adzhubei","year":"2010","journal-title":"Nat. Methods"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1158\/1535-7163.MCT-07-2422","article-title":"Medullary Thyroid Cancer: Targeting the RET Kinase Pathway with Sorafenib\/Tipifarnib","volume":"7","author":"Hong","year":"2008","journal-title":"Mol. Cancer Ther."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1038\/s41574-021-00470-9","article-title":"The Importance of the RET Gene in Thyroid Cancer and Therapeutic Implications","volume":"17","author":"Salvatore","year":"2021","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Sahakian, N., Castinetti, F., and Romanet, P. (2023). Molecular Basis and Natural History of Medullary Thyroid Cancer: It Is (Almost) All in the RET. Cancers, 15.","DOI":"10.3390\/cancers15194865"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1210\/endrev\/bnad013","article-title":"Medullary Thyroid Cancer: Updates and Challenges","volume":"44","author":"Gild","year":"2023","journal-title":"Endocr. Rev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1007\/s12020-023-03368-w","article-title":"Looking for RET Alterations in Thyroid Cancer: Clinical Relevance, Methodology and Timing","volume":"81","author":"Elisei","year":"2023","journal-title":"Endocrine"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2195","DOI":"10.1210\/clinem\/dgac325","article-title":"Somatic RET Indels in Sporadic Medullary Thyroid Cancer: Prevalence and Response to Selpercatinib","volume":"107","author":"Elisei","year":"2022","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1920","DOI":"10.1002\/cncr.28661","article-title":"RET Gene Mutations (Genotype and Phenotype) of Multiple Endocrine Neoplasia Type 2 and Familial Medullary Thyroid Carcinoma","volume":"120","author":"Krampitz","year":"2014","journal-title":"Cancer"}],"container-title":["Current Issues in Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1467-3045\/47\/7\/560\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:11:47Z","timestamp":1760033507000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1467-3045\/47\/7\/560"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,18]]},"references-count":24,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2025,7]]}},"alternative-id":["cimb47070560"],"URL":"https:\/\/doi.org\/10.3390\/cimb47070560","relation":{},"ISSN":["1467-3045"],"issn-type":[{"type":"electronic","value":"1467-3045"}],"subject":[],"published":{"date-parts":[[2025,7,18]]}}}