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Distant metastasis (DM) of PTC is uncommon, but when it occurs, it significantly decreases the survival of PTC patients. The molecular mechanisms of DM in PTC have not been systematically studied. We performed whole exome sequencing and GeneseeqPrime (425 genes) panel sequencing of the primary tumor, plasma and matched white blood cell samples from 20 PTC with DM and 46 PTC without DM. We identified somatic mutations, gene fusions and copy number alterations and analyzed their relationships with DM of PTC. <jats:italic>BRAF\u2010V600E<\/jats:italic> was identified in 73% of PTC, followed by <jats:italic>RET<\/jats:italic> fusions (14%) in a mutually exclusive manner (<jats:italic>P<\/jats:italic> &lt; 0.0001). We found that gene fusions (<jats:italic>RET<\/jats:italic>, <jats:italic>ALK<\/jats:italic> or <jats:italic>NTRK1<\/jats:italic>) (<jats:italic>P<\/jats:italic> &lt; 0.01) and chromosome 22q loss (<jats:italic>P<\/jats:italic> &lt; 0.01) were independently associated with DM in both univariate and multivariate analyses. A nomogram model consisting of chromosome 22q loss, gene fusions and three clinical variables was built for predicting DM in PTC (C\u2010index\u00a0=\u00a00.89). The plasma circulating tumor DNA (ctDNA) detection rate in PTC was only 38.9%; however, it was significantly associated with the metastatic status (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.04), tumor size (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.001) and invasiveness (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.01). In conclusion, gene fusions and chromosome 22q loss were independently associated with DM in PTC and could serve as molecular biomarkers for predicting DM. The ctDNA detection rate was low in non\u2013DM PTC but significantly higher in PTC with DM.<\/jats:p>","DOI":"10.1111\/cas.14389","type":"journal-article","created":{"date-parts":[[2020,3,18]],"date-time":"2020-03-18T20:57:37Z","timestamp":1584565057000},"page":"2163-2173","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":56,"title":["Genomic landscape of metastatic papillary thyroid carcinoma and novel biomarkers for predicting distant metastasis"],"prefix":"10.1111","volume":"111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5644-5602","authenticated-orcid":false,"given":"Xiabin","family":"Lan","sequence":"first","affiliation":[{"name":"Department of Head and Neck Surgery Cancer Hospital of the University of Chinese Academy of Sciences Zhejiang Cancer Hospital Hangzhou China"},{"name":"Key Laboratory of Head &amp; Neck Cancer Translational Research of Zhejiang Province Institute of Cancer and Basic Medicine Chinese Academy of Sciences Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5774-8755","authenticated-orcid":false,"given":"Hua","family":"Bao","sequence":"additional","affiliation":[{"name":"Translational Medicine Research Institute Geneseeq Technology Toronto ON Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyang","family":"Ge","sequence":"additional","affiliation":[{"name":"Key Laboratory of Head &amp; Neck Cancer Translational Research of Zhejiang Province Institute of Cancer and Basic Medicine Chinese Academy of Sciences Hangzhou China"},{"name":"Heartland Christian School Columbiana OH USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Cao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Head &amp; Neck Cancer Translational Research of Zhejiang Province Institute of Cancer and Basic Medicine Chinese Academy of Sciences Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1256-5343","authenticated-orcid":false,"given":"Xiaojun","family":"Fan","sequence":"additional","affiliation":[{"name":"Translational Medicine Research Institute Geneseeq Technology Toronto ON Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qihong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Zhejiang Chinese Medical University Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaihua","family":"Liu","sequence":"additional","affiliation":[{"name":"Nanjing Geneseeq Technology Inc. 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