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Therefore, we comprehensively characterized advanced, metastatic, radioiodine\u2010resistant (RAIR) thyroid carcinomas at the molecular level in the context of histologic heterogeneity with the aim to identify potentially actionable mutations that may guide the use of specific tyrosine kinase inhibitor (TKI) treatment. Whole exome sequencing (WES) was applied to 29 macrodissected tissue samples of histologically heterogeneous and homogeneous areas, lymph node and lung metastases from six clinically and histologically well\u2010characterized metastatic RAIR thyroid cancer patients with structural incomplete response to treatment. WES data were analyzed to identify potential driver mutations in oncogenic pathways, copy number alterations, microsatellite instability, mutant\u2010allele tumor heterogeneity, and the relevance of histologic heterogeneity to molecular profiling. In addition to known driver mutations in <jats:italic>BRAF<\/jats:italic>, <jats:italic>NRAS<\/jats:italic>, <jats:italic>EIF1AX<\/jats:italic>, <jats:italic>NCOA4\u2010RET<\/jats:italic>, and <jats:italic>TERT<\/jats:italic>, further potentially actionable drivers were identified in <jats:italic>AKT1<\/jats:italic>, <jats:italic>ATM<\/jats:italic>, <jats:italic>E2F1<\/jats:italic>, <jats:italic>HTR2A<\/jats:italic>, and <jats:italic>MLH3<\/jats:italic>. The analysis of the evolutionary history of the mutations and the reconstruction of the molecular phylogeny of the cancers show a remarkable association between histologic and molecular heterogeneity. A comprehensive molecular analysis of the primary tumor guided by histologic analysis may help to better stratify patients for precision medicine approaches. Given the association between the molecular and the histologic heterogeneity, the selection of tumor samples for molecular analysis should be based on meticulous histologic evaluation of the entire tumor.<\/jats:p>","DOI":"10.1002\/gcc.22949","type":"journal-article","created":{"date-parts":[[2021,3,22]],"date-time":"2021-03-22T13:50:45Z","timestamp":1616421045000},"page":"531-545","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Histology\u2010based molecular profiling improves mutation detection for advanced thyroid cancer"],"prefix":"10.1002","volume":"60","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4732-2934","authenticated-orcid":false,"given":"Markus","family":"Eszlinger","sequence":"first","affiliation":[{"name":"Departments of Oncology, Pathology and Laboratory Medicine, Biochemistry and Molecular Biology, and Arnie Charbonneau Cancer Institute Cumming School of Medicine, University of Calgary  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