{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T11:43:29Z","timestamp":1791546209354,"version":"4.3.4"},"reference-count":25,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2019,12,1]],"date-time":"2019-12-01T00:00:00Z","timestamp":1575158400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Histopathology"],"published-print":{"date-parts":[[2020,2]]},"abstract":"<jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>\n                      Colorectal carcinomas (CRC) with mismatch repair (MMR) deficiency have increased tumour mutation burden and respond to immune check\u2010point inhibitor therapy. The Cancer Genome Atlas identified hypermutated CRCs with somatic mutations in DNA polymerase \u03b5 (\n                      <jats:italic>POLE<\/jats:italic>\n                      ) with mutation burdens exceeding that of MMR\u2010deficient CRCs.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>\n                      To identify the morphological, immunophenotypical and molecular features of\n                      <jats:italic>POLE<\/jats:italic>\n                      \u2010mutated CRCs, 63 consecutive MMR\u2010intact CRCs were evaluated by Sanger sequencing for\n                      <jats:italic>POLE<\/jats:italic>\n                      exonuclease domain mutations in exons 9, 11, 13 and 14 and confirmed by next\u2010generation sequencing. Tumour immune microenvironment and IMMUNOSCORE\u00ae\n                      <jats:sup>1<\/jats:sup>\n                      were assessed in\n                      <jats:italic>POLE<\/jats:italic>\n                      \u2010mutated CRCs using immunohistochemistry to detect CD3\n                      <jats:sup>+<\/jats:sup>\n                      \/CD8\n                      <jats:sup>+<\/jats:sup>\n                      tumour\u2010infiltrating lymphocytes and compared to 59 non\u2010\n                      <jats:italic>POLE<\/jats:italic>\n                      mutated MMR\u2010intact CRC, 10 non\u2010\n                      <jats:italic>POLE<\/jats:italic>\n                      mutated MMR\u2010deficient CRCs and 223 normal colonic mucosa.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      A total of 4.8% CRC (four MMR\u2010intact primary and one MMR\u2010intact metastasis) harboured\n                      <jats:italic>POLE<\/jats:italic>\n                      mutations in amino acid 286 in exon 9 (p.P286R) or exon 13 (p.V411L).\n                      <jats:italic>POLE<\/jats:italic>\n                      \u2010mutated CRCs arose in the transverse colon and rectum, were male\u2010predominant, younger and showed increased tumour\u2010infiltrating lymphocytes and immune cells at the tumour\u2013stromal interface. The patient with metastatic\n                      <jats:italic>POLE<\/jats:italic>\n                      \u2010mutated CRC was placed on PD\u20101 inhibitor treatment with marked and sustained response. These data indicate that\n                      <jats:italic>POLE<\/jats:italic>\n                      \u2010mutated CRCs have hypermutated phenotypes despite MMR\u2010intact status, with mutation burdens higher than that in microsatellite\u2010unstable CRCs. Given the recent approval for treatment of microsatellite\u2010unstable cancer with immune check\u2010point inhibitors, assessment of\n                      <jats:italic>POLE<\/jats:italic>\n                      status may help to guide therapeutic decisions for hypermutated tumours with intact MMR that would otherwise be missed by routine testing.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/his.13984","type":"journal-article","created":{"date-parts":[[2019,9,3]],"date-time":"2019-09-03T15:30:07Z","timestamp":1567524607000},"page":"366-374","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Morphological, immunophenotypical and molecular features of hypermutation in colorectal carcinomas with mutations in DNA polymerase \u03b5 (\n                    <scp>\n                      <i>POLE<\/i>\n                    <\/scp>\n                    )"],"prefix":"10.1111","volume":"76","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6320-0905","authenticated-orcid":false,"given":"Erna","family":"Forg\u00f3","sequence":"first","affiliation":[{"name":"Department of Pathology Stanford University School of Medicine Stanford CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3265-694X","authenticated-orcid":false,"given":"Adam J","family":"Gomez","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Arizona College of Medicine\u2013Phoenix Phoenix AZ USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Steiner","sequence":"additional","affiliation":[{"name":"Department of Pathology Stanford University School of Medicine Stanford CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5380-303X","authenticated-orcid":false,"given":"James","family":"Zehnder","sequence":"additional","affiliation":[{"name":"Department of Pathology Stanford University School of Medicine Stanford CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0935-7300","authenticated-orcid":false,"given":"Teri A","family":"Longacre","sequence":"additional","affiliation":[{"name":"Department of Pathology Stanford University School of Medicine Stanford CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,12]]},"reference":[{"key":"e_1_2_8_2_1","volume-title":"WHO classification of tumours of the digestive system","author":"Bosman Fred T","year":"2010"},{"key":"e_1_2_8_3_1","volume-title":"Surgical pathology of the GI tract, liver, biliary tract, and pancreas","author":"Odze 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