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In this study, dMMR CRCs were screened for oncogene fusions using sequential DNA and RNA next generation sequencing (NGS).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Comprehensive analysis of fusion variants, genetic profiles and clinicopathological features in fusion-positive dMMR CRCs was performed. Among 193 consecutive dMMR CRCs, 39 cases were identified as <jats:italic>MLH1<\/jats:italic><jats:sup>me+<\/jats:sup><jats:italic>BRAF\/RAS<\/jats:italic> wild-type. Eighteen fusion-positive cases were detected by DNA NGS, all of which were <jats:italic>MLH1<\/jats:italic><jats:sup>me+<\/jats:sup> and <jats:italic>BRAF\/RAS<\/jats:italic> wild-type. RNA NGS was sequentially conducted in the remaining 21 <jats:italic>MLH1<\/jats:italic><jats:sup>me+<\/jats:sup><jats:italic>BRAF\/RAS<\/jats:italic> wild-type cases lacking oncogenic fusions by DNA NGS, and revealed four additional fusions, increasing the proportion of fusion-positive tumors from 46% (18\/39) to 56% (22\/39) in <jats:italic>MLH1<\/jats:italic><jats:sup>me+<\/jats:sup><jats:italic>BRAF\/RAS<\/jats:italic> wild-type dMMR cases. All 22 fusions were found to involve RTK-RAS pathway. Most fusions affected targetable receptor tyrosine kinases, including <jats:italic>NTRK1<\/jats:italic>(9\/22, 41%), <jats:italic>NTRK3<\/jats:italic>(5\/22, 23%), <jats:italic>ALK<\/jats:italic>(3\/22, 14%), <jats:italic>RET<\/jats:italic>(2\/22, 9%) and <jats:italic>MET<\/jats:italic>(1\/22, 5%), whilst only two fusions affected mitogen-activated protein kinase cascade components <jats:italic>BRAF<\/jats:italic> and <jats:italic>MAPK1<\/jats:italic>, respectively. <jats:italic>RNF43<\/jats:italic> was identified as the most frequently mutated genes, followed by <jats:italic>APC<\/jats:italic>, <jats:italic>TGFBR2<\/jats:italic>, <jats:italic>ATM<\/jats:italic>, <jats:italic>BRCA2<\/jats:italic> and <jats:italic>FBXW7<\/jats:italic>. The vast majority (19\/22, 86%) displayed alterations in key WNT pathway components, whereas none harbored additional mutations in RTK-RAS pathway. In addition, fusion-positive tumors were typically diagnosed in elder patients and predominantly right-sided, and showed a significantly higher preponderance of hepatic flexure localization (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.001) and poor differentiation (<jats:italic>P<\/jats:italic>\u2009=\u20090.019), compared to fusion-negative <jats:italic>MLH1<\/jats:italic><jats:sup>me+<\/jats:sup> CRCs.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>We proved that sequential DNA and RNA NGS was highly effective for fusion detection in dMMR CRCs, and proposed an optimized practical fusion screening strategy. We further revealed that dMMR CRCs harboring oncogenic fusion was a genetically and clinicopathologically distinctive subgroup, and justified more precise molecular subtyping for personalized therapy.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12967-021-03108-6","type":"journal-article","created":{"date-parts":[[2021,10,17]],"date-time":"2021-10-17T22:07:17Z","timestamp":1634508437000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Comprehensive analysis of oncogenic fusions in mismatch repair deficient colorectal carcinomas by sequential DNA and RNA next generation sequencing"],"prefix":"10.1186","volume":"19","author":[{"given":"Jing","family":"Wang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruiyu","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junjie","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuting","family":"Yi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoding","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingci","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hui","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junliang","family":"Lu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cami","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huanwen","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhiyong","family":"Liang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,10,17]]},"reference":[{"issue":"1","key":"3108_CR1","doi-asserted-by":"publisher","first-page":"7","DOI":"10.3322\/caac.21590","volume":"70","author":"RL Siegel","year":"2020","unstructured":"Siegel RL, Miller KD, Jemal A. 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