{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T13:19:25Z","timestamp":1792588765163,"version":"4.5.0"},"reference-count":50,"publisher":"BMJ","issue":"10","license":[{"start":{"date-parts":[[2021,10,3]],"date-time":"2021-10-03T00:00:00Z","timestamp":1633219200000},"content-version":"unspecified","delay-in-days":2,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2020R1A2C2006815"],"award-info":[{"award-number":["2020R1A2C2006815"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2021,8,20]]},"published-print":{"date-parts":[[2021,10]]},"abstract":"<jats:sec>\n                  <jats:title>Introduction<\/jats:title>\n                  <jats:p>Mismatch repair (MMR)-deficient and DNA polymerase epsilon (<jats:italic>POLE<\/jats:italic>)-mutated tumors exhibit a high tumor mutation burden (TMB) and have been proven to be associated with good responses to immune checkpoint inhibitor treatments. However, the relationship between mutational characteristics of MMR-deficient and <jats:italic>POLE<\/jats:italic>-mutated tumors and the spatial architecture of tumor-infiltrating lymphocytes (TILs) has not been fully evaluated.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We retrieved microsatellite instability-high (MSI-high, N=20) and <jats:italic>POLE<\/jats:italic>-mutated (N=47) cases from the clinical next-generation sequencing cohort at Asan Medical Center. Whole-slide immunostaining for CD3, CD4, CD8, FoxP3 and PD-1 were performed with tissue samples of colorectal and gastric cancer (N=24) and the tumor-positive TIL cell densities were correlated with the tumor\u2019s mutational features. The findings were compared with the results of similar analyses in The Cancer Genome Atlas-Colorectal Adenocarcinoma (TCGA-COADREAD) cohort (N=592).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>The MSI-high group showed significantly higher overall TMBs with a number of insertion\/deletion (indel) mutations relative to the <jats:italic>POLE<\/jats:italic>-mutated group (median TMB; 83.6 vs 12.5\/Mb). Oncogenic\/likely-oncogenic <jats:italic>POLE<\/jats:italic> mutations were identified with ultrahypermutations (\u2265100 mutations\/Mb) (2\/47, 4.3%). Concurrent <jats:italic>POLE<\/jats:italic> mutations of unknown significance and MSI-high cases were identified in eight cases (8\/67, 11%), and two of these colorectal cancers had multiple <jats:italic>POLE<\/jats:italic> mutations, showing an ultramutated phenotype (378.1 and 484.4\/Mb) and low indel mutation burdens with complete loss of MSH-6 or PMS-2, which was similar to the mutational profile of the <jats:italic>POLE<\/jats:italic>-inactivated tumors. Intratumoral CD3-positive, CD4-positive, CD8-positive, FoxP3-positive and PD-1-positive TIL cell densities were more strongly correlated with the indel mutation burden than with the total TMB (correlation coefficient, 0.61\u20130.73 vs 0.23\u20130.38). In addition, PI3K\/AKT\/mTOR pathway mutations were commonly found in MSI-high tumors (75%) but not in <jats:italic>POLE<\/jats:italic>-mutated tumors.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Indel mutation burden rather than total TMB could serve as a predictor of high TILs in both MSI-high and <jats:italic>POLE<\/jats:italic>-mutated tumors. Multiple uncharacterized\/non-pathogenic <jats:italic>POLE<\/jats:italic> mutations occurring via MMR deficiency within MSI-high tumors may have combined pathogenic roles. A mutated PI3K\/AKT\/mTOR pathway may be a biomarker that can be used to stratify patients with advanced MSI-high tumors for immune therapy.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jitc-2021-002797","type":"journal-article","created":{"date-parts":[[2021,10,4]],"date-time":"2021-10-04T18:33:04Z","timestamp":1633372384000},"page":"e002797","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":46,"title":["Distinct mutational profile and immune microenvironment in microsatellite-unstable and <i>POLE<\/i>-mutated tumors"],"prefix":"10.1136","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9486-9214","authenticated-orcid":false,"given":"Hee Sang","family":"Hwang","sequence":"first","affiliation":[{"name":"Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South 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