{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T23:48:15Z","timestamp":1778716095446,"version":"3.51.4"},"reference-count":42,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2023,2,23]],"date-time":"2023-02-23T00:00:00Z","timestamp":1677110400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Japan Society for the Promotion of Science Grants-in-Aid for Scientific Researc","award":["21K09472"],"award-info":[{"award-number":["21K09472"]}]},{"name":"the Japan Society for the Promotion of Science Grants-in-Aid for Scientific Researc","award":["22K09596"],"award-info":[{"award-number":["22K09596"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CIMB"],"abstract":"<jats:p>Background: Since malignant struma ovarii is a very rare disease, its carcinogenic mechanism has not been elucidated. Here, we sought to identify the genetic lesions that may have led to the carcinogenesis of a rare case of malignant struma ovarii (follicular carcinoma) with peritoneal dissemination. Methods: DNA was extracted from the paraffin-embedded sections of normal uterine tissues and malignant struma ovarii for genetic analysis. Whole-exome sequencing and DNA methylation analysis were then performed. Results: Germline variants of RECQL4, CNTNAP2, and PRDM2, which are tumor-suppressor genes, were detected by whole-exome sequencing. Somatic uniparental disomy (UPD) was also observed in these three genes. Additionally, the methylation of FRMD6-AS2, SESN3, CYTL1, MIR4429, HIF3A, and ATP1B2, which are associated with tumor growth suppression, was detected by DNA methylation analysis. Conclusions: Somatic UPD and DNA methylation in tumor suppressor genes may be associated with the pathogenesis of malignant struma ovarii. To our knowledge, this is the first report of whole-exome sequencing and DNA methylation analysis in malignant struma ovarii. Genetic and DNA methylation analysis may help elucidate the mechanism of carcinogenesis in rare diseases and guide treatment decisions.<\/jats:p>","DOI":"10.3390\/cimb45030118","type":"journal-article","created":{"date-parts":[[2023,2,23]],"date-time":"2023-02-23T03:56:58Z","timestamp":1677124618000},"page":"1843-1851","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Identifying the Carcinogenic Mechanism of Malignant Struma Ovarii Using Whole-Exome Sequencing and DNA Methylation Analysis"],"prefix":"10.3390","volume":"45","author":[{"given":"Hitomi","family":"Yamashita","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo 693-8501, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3250-3097","authenticated-orcid":false,"given":"Kentaro","family":"Nakayama","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo 693-8501, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kosuke","family":"Kanno","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo 693-8501, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomoka","family":"Ishibashi","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo 693-8501, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masako","family":"Ishikawa","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo 693-8501, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seiya","family":"Sato","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo 693-8501, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Koji","family":"Iida","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo 693-8501, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sultana","family":"Razia","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo 693-8501, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8986-6147","authenticated-orcid":false,"given":"Satoru","family":"Kyo","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo 693-8501, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1080\/00313020601123979","article-title":"The Enigma of struma ovarii","volume":"39","author":"Roth","year":"2007","journal-title":"Pathology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/S0090-8258(03)00142-2","article-title":"Malignant struma ovarii: A case report of laparoscopic management","volume":"90","author":"Volpi","year":"2003","journal-title":"Gynecol. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1006\/gyno.1999.5355","article-title":"Malignant struma ovarii: Two case reports and a review of the literature","volume":"73","author":"Dardik","year":"1999","journal-title":"Gynecol. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1089\/thy.2014.0328","article-title":"Malignant struma ovarii: A population-level analysis of a large series of 68 patients","volume":"25","author":"Goffredo","year":"2015","journal-title":"Thyroid"},{"key":"ref_5","unstructured":"(2023, February 17). Genetic Analysis of Cancer. Available online: https:\/\/www.mesw.co.jp\/solution\/itsolution\/plessision.html."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"7407","DOI":"10.1002\/cam4.3383","article-title":"Clinical implications of next-generation sequencing-based panel tests for malignant ovarian tumors","volume":"9","author":"Saotome","year":"2020","journal-title":"Cancer Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1006\/gyno.2001.6315","article-title":"Malignant struma ovarii with thyrotoxicosis","volume":"82","author":"Matsuda","year":"2001","journal-title":"Gynecol. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"389","DOI":"10.2217\/epi.15.114","article-title":"Validation of a DNA methylation microarray for 850,000 CpG sites of the human genome enriched in enhancer sequences","volume":"8","author":"Moran","year":"2016","journal-title":"Epigenomics"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"117254","DOI":"10.1016\/j.lfs.2020.117254","article-title":"The tumor suppressive effect of long non-coding RNA FRMD6-AS2 in uteri corpus endometrial carcinoma","volume":"243","author":"Wang","year":"2020","journal-title":"Life Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2685","DOI":"10.1016\/j.bbadis.2019.07.011","article-title":"Sesn3 deficiency promotes carcinogen-induced hepatocellular carcinoma via regulation of the hedgehog pathyway","volume":"1865","author":"Liu","year":"2019","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e1577126","DOI":"10.1080\/2162402X.2019.1577126","article-title":"CYTL1 inhibits tumor metastasis with decreasing STAT3 phosphorylation","volume":"8","author":"Wang","year":"2019","journal-title":"Oncoimmunology"},{"key":"ref_12","first-page":"8722","article-title":"MiR-4429 suppresses the malignant development of ovarian cancer by targeting YOD1","volume":"24","author":"Zhu","year":"2020","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1016\/j.orcp.2020.10.001","article-title":"HIF3A DNA methylation, obesity and weight gain, and breast cancer risk among Mexican American women","volume":"14","author":"Shen","year":"2020","journal-title":"Obes. Res. Clin. Pract."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/jbt.22749","article-title":"Upregulation of lncRNA DARS-AS1 accelerates tumor malignancy in cervical cancer by activating cGMP-PKG pathway","volume":"35","author":"Kong","year":"2021","journal-title":"J. Biochem. Mol. Toxicol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1016\/j.ygyno.2004.06.003","article-title":"Struma ovarii with a focus of papillary thyroid cancer: A case report and review of the literature","volume":"94","author":"Makani","year":"2004","journal-title":"Gynecol. Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3339","DOI":"10.1111\/jog.14902","article-title":"Malignant struma ovarii: From case to analysis","volume":"47","author":"Ayhan","year":"2021","journal-title":"J. Obstet. Gynaecol. Res."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Li, S., Yang, T., Xiang, Y., Li, X., Zhang, L., and Deng, S. (2021). Clinical characteristics and survival outcomes of malignant struma ovarii confined to the ovary. BMC Cancer, 21.","DOI":"10.1186\/s12885-021-08118-7"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1097\/PGP.0b013e3181bfb133","article-title":"Natural history of biologically malignant struma ovarii: Analysis of 27 cases with extraovarian spread","volume":"29","author":"Bean","year":"2010","journal-title":"Int. J. Gynecol. Pathol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2458","DOI":"10.3892\/ol.2014.2587","article-title":"Long-term survival in metastatic malignant struma ovarii treated with oral chemotherapy: A case report","volume":"8","author":"Ukita","year":"2014","journal-title":"Oncol. Lett."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1677\/erc.0.0110131","article-title":"Prognostic factors of papillary and follicular thyroid cancer: Differences in an iodine-replete endemic goiter region","volume":"11","author":"Passler","year":"2004","journal-title":"Endocr. Relat. Cancer"},{"key":"ref_21","unstructured":"Cancer Genome Atlas Research Network (2014). Integrated genomic characterization of papillary thyroid carcinoma. Cell, 159, 676\u2013690."},{"key":"ref_22","first-page":"1454","article-title":"High prevalence of BRAF mutations in thyroid cancer: Genetic evidence for constitutive activation of the RET\/PTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma","volume":"63","author":"Kimura","year":"2003","journal-title":"Cancer Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"54","DOI":"10.3389\/fendo.2012.00054","article-title":"RET\/PTC Translocations and Clinico-Pathological Features in Human Papillary Thyroid Carcinoma","volume":"3","author":"Romei","year":"2012","journal-title":"Front. Endocrinol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1007\/s12022-009-9097-8","article-title":"RAS mutation-positive follicular variant of papillary thyroid carcinoma arising in a struma ovarii","volume":"21","author":"Coyne","year":"2010","journal-title":"Endocr. Pathol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1068","DOI":"10.1172\/JCI200522758","article-title":"The RET\/PTC-RAS-BRAF linear signaling cascade mediates the motile and mitogenic phenotype of thyroid cancer cells","volume":"115","author":"Melillo","year":"2005","journal-title":"J. Clin. Investig."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.mce.2010.11.009","article-title":"Well differentiated follicular thyroid neoplasia: Impact of molecular and technological advances on detection, monitoring and treatment","volume":"332","author":"Gianoukakis","year":"2011","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1007\/s12022-007-0022-8","article-title":"Follicular variant papillary thyroid carcinoma arising in struma ovarii","volume":"18","author":"Saleh","year":"2007","journal-title":"Endocr. Pathol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1337","DOI":"10.1097\/PAS.0b013e31802f5404","article-title":"BRAF in papillary thyroid carcinoma of ovary (struma ovarii)","volume":"31","author":"Schmidt","year":"2007","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Stanojevic, B., Dzodic, R., Saenko, V., Milovanovic, Z., Krstevski, V., Radlovic, P., Buta, M., Rulic, B., Todorovic, L., and Dimitrijevic, B. (2012). Unilateral follicular variant of papillary thyroid carcinoma with unique KRAS mutation in struma ovarii in bilateral ovarian teratoma: A rare case report. BMC Cancer, 12.","DOI":"10.1186\/1471-2407-12-224"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1007\/BF03401528","article-title":"Malignant struma ovarii harboring a unique NRAS mutation: Case report and review of the literature","volume":"16","author":"Gobitti","year":"2017","journal-title":"Hormones"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1001\/jama.2013.8589","article-title":"BRAF V600E mutation and papillary thyroid cancer","volume":"310","author":"Ciarrocchi","year":"2013","journal-title":"JAMA"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1007\/s12022-015-9394-3","article-title":"Novel BRAF and KRAS mutations in papillary thyroid carcinoma arising in struma ovarii","volume":"26","author":"Tan","year":"2015","journal-title":"Endocr. Pathol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1007\/s12020-020-02438-7","article-title":"Malignant struma ovarii: Next-generation sequencing of six cases revealed Nras, Braf, and Jak3 mutations","volume":"71","author":"Poli","year":"2021","journal-title":"Endocrine"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"E338","DOI":"10.1210\/jc.2013-2792","article-title":"RNA sequencing identifies multiple fusion transcripts, differentially expressed genes, and reduced expression of immune function genes in BRAF(V600E) mutant vs BRAF wild-type papillary thyroid carcinoma","volume":"99","author":"Smallridge","year":"2014","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Kim, K., Jeon, S., Kim, T.M., and Jung, C.K. (2018). Immune gene signature delineates a subclass of papillary thyroid cancer with unfavorable clinical outcomes. Cancers, 10.","DOI":"10.3390\/cancers10120494"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"100498","DOI":"10.1016\/j.gore.2019.100498","article-title":"Malignant struma ovarii presenting with follicular carcinoma: A case report with molecular analysis","volume":"30","author":"Tsukada","year":"2019","journal-title":"Gynecol. Oncol. Rep."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1159\/000516568","article-title":"Human RecQL4 as a novel molecular target for cancer therapy","volume":"161","author":"Balajee","year":"2021","journal-title":"Cytogenet. Genome Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"6138","DOI":"10.1038\/onc.2010.342","article-title":"The CASPR2 cell adhesion molecule functions as a tumor suppressor gene in glioma","volume":"29","author":"Bralten","year":"2010","journal-title":"Oncogene"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Zhang, C., Zhu, Q., He, H., Jiang, L., Qiang, Q., Hu, L., Hu, G., Jiang, Y., Ding, X., and Lu, Y. (2015). RIZ1: A potential tumor suppressor in glioma. BMC Cancer, 15.","DOI":"10.1186\/s12885-015-2023-1"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1038\/s41586-022-05496-1","article-title":"Ovarian cancer mutational processes drive site-specific immune evasion","volume":"612","author":"Uhlitz","year":"2022","journal-title":"Nature"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1853","DOI":"10.1038\/s41588-022-01230-9","article-title":"The genomic and immune landscape of long-term survivors of high-grade serous ovarian cancer","volume":"54","author":"Garsed","year":"2022","journal-title":"Nat. Genet."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1038\/s41586-022-05249-0","article-title":"Single-cell genomic variation induced by mutational processes in cancer","volume":"612","author":"Funnell","year":"2022","journal-title":"Nature"}],"container-title":["Current Issues in Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1467-3045\/45\/3\/118\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:40:07Z","timestamp":1760121607000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1467-3045\/45\/3\/118"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,23]]},"references-count":42,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2023,3]]}},"alternative-id":["cimb45030118"],"URL":"https:\/\/doi.org\/10.3390\/cimb45030118","relation":{},"ISSN":["1467-3045"],"issn-type":[{"value":"1467-3045","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,23]]}}}