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We investigated the frequency of DNA repair GAs in gallbladder cancer (GBC), association with tumor mutational burden (TMB), microsatellite instability (MSI), programmed cell death protein 1 (PD-1), and its ligand (PD-L1) expression. Comprehensive genomic profiling (CGP) of 760 GBC was performed. We investigated GAs in\u00a019 DNA repair genes including direct DNA repair genes (<jats:italic>ATM<\/jats:italic>, <jats:italic>ATR<\/jats:italic>, <jats:italic>BRCA1<\/jats:italic>, <jats:italic>BRCA2<\/jats:italic>, <jats:italic>FANCA<\/jats:italic>, <jats:italic>FANCD2<\/jats:italic>, <jats:italic>MLH1<\/jats:italic>, <jats:italic>MSH2<\/jats:italic>, <jats:italic>MSH6<\/jats:italic>, <jats:italic>PALB2<\/jats:italic>, <jats:italic>POLD1<\/jats:italic>, <jats:italic>POLE<\/jats:italic>, <jats:italic>PRKDC<\/jats:italic>, and\u00a0<jats:italic>RAD50<\/jats:italic>) and caretaker genes (<jats:italic>BAP1<\/jats:italic>, <jats:italic>CDK12<\/jats:italic>, <jats:italic>MLL3<\/jats:italic>, <jats:italic>TP53<\/jats:italic>, and <jats:italic>BLM<\/jats:italic>) and classified patients into 3 groups based on TMB level: low (&lt;\u20095.5 mutations\/Mb), intermediate (5.5\u201319.5 mutations\/Mb), and high (\u2265\u200919.5 mutations\/Mb). We assessed MSI status and PD-1 &amp; PD-L1 expression. 658 (86.6%) had at least 1 actionable GA. Direct DNA repair gene GAs were identified in 109 patients (14.2%), while 476 (62.6%) had GAs in caretaker genes. Both direct and caretaker DNA repair GAs were significantly associated with high TMB (<jats:italic>P<\/jats:italic>\u2009=\u20090.0005 and 0.0001, respectively). Tumor PD-L1 expression was positive in 119 (15.6%), with 17 (2.2%) being moderate or high. DNA repair GAs are relatively frequent in GBC and associated with coexisting actionable mutations and a high TMB.<\/jats:p>","DOI":"10.1038\/s41598-020-77939-6","type":"journal-article","created":{"date-parts":[[2020,12,16]],"date-time":"2020-12-16T11:06:18Z","timestamp":1608116778000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":49,"title":["Genomic profiling reveals high frequency of DNA repair genetic aberrations in gallbladder cancer"],"prefix":"10.1038","volume":"10","author":[{"given":"Reham","family":"Abdel-Wahab","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy A.","family":"Yap","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Russell","family":"Madison","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shubham","family":"Pant","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Cooke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haitao","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanios","family":"Bekaii-Saab","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elif","family":"Karatas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lawrence N.","family":"Kwong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Funda","family":"Meric-Bernstam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitesh","family":"Borad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milind","family":"Javle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,12,16]]},"reference":[{"key":"77939_CR1","doi-asserted-by":"publisher","first-page":"349","DOI":"10.3322\/canjclin.51.6.349","volume":"51","author":"EC Lazcano-Ponce","year":"2001","unstructured":"Lazcano-Ponce, E. 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