{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T03:51:01Z","timestamp":1782186661558,"version":"3.54.5"},"reference-count":43,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2020,4,25]],"date-time":"2020-04-25T00:00:00Z","timestamp":1587772800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["1UM1CA186691\u201001"],"award-info":[{"award-number":["1UM1CA186691\u201001"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Medicine"],"published-print":{"date-parts":[[2020,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Selective IDH1 and IDH2 inhibitors have been approved for targeted therapy of acute myeloid leukemia. Clinical trials for solid tumors with <jats:italic>IDH1<\/jats:italic> and <jats:italic>IDH2<\/jats:italic> (<jats:italic>IDH1<\/jats:italic>\/<jats:italic>2<\/jats:italic>) mutations are ongoing. Reports of <jats:italic>IDH1<\/jats:italic>\/<jats:italic>2<\/jats:italic>\u2010mutated non\u2013small cell lung cancers (NSCLCs), however, are limited.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We evaluated <jats:italic>IDH1<\/jats:italic>\/<jats:italic>2<\/jats:italic> mutations in 1,924 NSCLC specimens (92% adenocarcinoma) using a next\u2010generation sequencing assay.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Retrospective quality assessments identified false detection of <jats:italic>IDH1<\/jats:italic> c.395G&gt;A (p.R132H) resulting from cytosine deamination (C:G\u2192T:A) artifact in one specimen. <jats:italic>IDH1<\/jats:italic>\/<jats:italic>2<\/jats:italic> mutations were detected in 9 (0.5%) adenocarcinomas taken by fine\u2010needle aspiration (n\u00a0=\u00a03), thoracentesis (n\u00a0=\u00a02) or core biopsy (n\u00a0=\u00a04). All nine adenocarcinomas showed high\u2010grade features. Extensive clear cell change, however, was not observed. High expression (50% or greater) of PD\u2010L1 was observed in two of five specimens examined. <jats:italic>IDH1<\/jats:italic>\/<jats:italic>2<\/jats:italic> mutations were associated with old age, smoking history, and coexisting <jats:italic>KRAS<\/jats:italic> mutation. Lower than expected variant allele frequency of <jats:italic>IDH1<\/jats:italic>\/<jats:italic>2<\/jats:italic> mutants and coexistence of <jats:italic>IDH1\/2<\/jats:italic> mutations with known trunk drivers in the <jats:italic>BRAF<\/jats:italic>, <jats:italic>EGFR,<\/jats:italic> and <jats:italic>KRAS<\/jats:italic> genes suggest they could be branching drivers leading to subclonal evolution in lung adenocarcinomas. Multiregional analysis of an adenocarcinoma harboring two <jats:italic>IDH2<\/jats:italic> mutations revealed parallel evolution originating from a <jats:italic>KRAS<\/jats:italic>\u2010mutated lineage, further supporting subclonal evolution promoted by <jats:italic>IDH1<\/jats:italic>\/<jats:italic>2<\/jats:italic> mutations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p><jats:italic>IDH1<\/jats:italic>\/<jats:italic>2<\/jats:italic> mutations in NSCLCs are uncommon. They occur in adenocarcinomas with high\u2010grade features and may be branching drivers leading to subclonal evolution. Accumulation of more <jats:italic>IDH1<\/jats:italic>\/<jats:italic>2<\/jats:italic>\u2010mutated NSCLCs is needed to clarify their clinicopathological characteristics and implications for targeted therapy.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cam4.3058","type":"journal-article","created":{"date-parts":[[2020,4,25]],"date-time":"2020-04-25T10:39:24Z","timestamp":1587811164000},"page":"4386-4394","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["<i>IDH1<\/i> and <i>IDH2<\/i> mutations in lung adenocarcinomas: Evidences of subclonal evolution"],"prefix":"10.1002","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6757-1172","authenticated-orcid":false,"given":"Erika F.","family":"Rodriguez","sequence":"first","affiliation":[{"name":"Department of Pathology Johns Hopkins University School of Medicine Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federico","family":"De Marchi","sequence":"additional","affiliation":[{"name":"Department of Pathology Johns Hopkins University School of Medicine Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Parvez M.","family":"Lokhandwala","sequence":"additional","affiliation":[{"name":"Department of Pathology Johns Hopkins University School of Medicine Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah","family":"Belchis","sequence":"additional","affiliation":[{"name":"Department of Pathology Johns Hopkins University School of Medicine Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rena","family":"Xian","sequence":"additional","affiliation":[{"name":"Department of Pathology Johns Hopkins University School of Medicine Baltimore MD USA"},{"name":"Department of Oncology Johns Hopkins University School of Medicine Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher 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