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Previous reports have revealed that primary gastrointestinal-DLBCL (pGI-DLBCL) harbors different genetic mutations from other nodal or extranodal DLBCL. However, the exonic mutation profile of pGI-DLBCL has not been fully addressed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We performed whole-exome sequencing of matched tumor tissues and blood samples from 53 pGI-DLBCL patients. The exonic mutation profiles were screened, and the correlations between genetic mutations and clinicopathological characteristics were analyzed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A total of 6,588 protein-altering events were found and the five most frequent mutated genes in our pGI-DLBCL cohort were<jats:italic>IGLL5<\/jats:italic>(47%),<jats:italic>TP53<\/jats:italic>(42%),<jats:italic>BTG2<\/jats:italic>(28%),<jats:italic>P2RY8<\/jats:italic>(26%) and<jats:italic>PCLO<\/jats:italic>(23%). Compared to the common DLBCL, significantly less or absence of<jats:italic>MYD88<\/jats:italic>(0%),<jats:italic>EZH2<\/jats:italic>(0%),<jats:italic>BCL2<\/jats:italic>(2%) or<jats:italic>CD79B<\/jats:italic>(8%) mutations were identified in pGI-DLBCL. The recurrent potential driver genes were mainly enriched in pathways related to signal transduction, infectious disease and immune regulation. In addition, HBV infection had an impact on the mutational signature in pGI-DLBCL, as positive HBsAg was significantly associated with the<jats:italic>TP53<\/jats:italic>and<jats:italic>LRP1B<\/jats:italic>mutations, two established tumor suppressor genes in many human cancers. Moreover,<jats:italic>IGLL5<\/jats:italic>and<jats:italic>LRP1B<\/jats:italic>mutations were significantly correlated with patient overall survival and could serve as two novel prognostic biomarkers in pGI-DLBCL.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our study provides a comprehensive view of the exonic mutation profile of the largest pGI-DLBCL cohort to date. The results could facilitate the clinical development of novel therapeutic and prognostic biomarkers for pGI-DLBCL.<\/jats:p><\/jats:sec>","DOI":"10.1186\/s40164-022-00325-7","type":"journal-article","created":{"date-parts":[[2022,10,15]],"date-time":"2022-10-15T09:02:56Z","timestamp":1665824576000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Whole-exome sequencing analysis identifies distinct mutational profile and novel prognostic biomarkers in primary gastrointestinal diffuse large B-cell lymphoma"],"prefix":"10.1186","volume":"11","author":[{"given":"Shan-Shan","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Hui","family":"Zhai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai-Ling","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting-Zhi","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tai-Yuan","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong-Mei","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Le-Xin","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Qin","family":"Gan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wan-Jia","family":"Hong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Fan","family":"Lian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,10,15]]},"reference":[{"issue":"1","key":"325_CR1","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1186\/s40164-021-00198-2","volume":"10","author":"M Keykhaei","year":"2021","unstructured":"Keykhaei M, Masinaei M, Mohammadi E, Azadnajafabad S, Rezaei N, Saeedi Moghaddam S, Rezaei N, Nasserinejad M, Abbasi-Kangevari M, Malekpour MR, Ghamari SH, Haghshenas R, Koliji K, Kompani F, Farzadfar F. 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