{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T15:41:29Z","timestamp":1787586089481,"version":"build-2736575974"},"reference-count":65,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T00:00:00Z","timestamp":1764806400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T00:00:00Z","timestamp":1764806400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["19KK0408"],"award-info":[{"award-number":["19KK0408"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["24K10123"],"award-info":[{"award-number":["24K10123"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Type B1 and B2 thymomas are lymphocyte\u2010rich malignant tumours with few somatic mutations in protein\u2010coding regions of the nuclear genome; nonetheless, noncoding regions remain uncharacterized. Here, we developed a method to isolate pure thymoma cells from lymphocyte\u2010rich tissues, and then performed genome\u2010wide deep sequencing. The total number of somatic mutations was ~80 times higher in noncoding regions than in coding regions in type B12 thymomas (1,671.3 versus 21.1 per case). Coding mutations were identified in epigenetic regulators, DNA repair genes, and some other genes. Nevertheless, 40% of the cases exhibited fewer than four nonsynonymous mutations in coding regions. A systematic noncoding analysis identified 405.0 mutations per case in cis\u2010regulatory elements and detected six recurrent mutations: one interferon regulatory factor (\n                    <jats:italic>IRF8<\/jats:italic>\n                    ), two E3 ubiquitin ligases (\n                    <jats:italic>UBR2<\/jats:italic>\n                    and\n                    <jats:italic>RNF213<\/jats:italic>\n                    ), and three intergenic regions. Tumour\u2010specific\/enriched mitochondrial heteroplasmic shift was observed in 90% of cases, with a significant proportion of mutations located in the D\u2010loop region. When tracing the evolutionary lineage of mtDNA mutation, the majority of cases can be explained by a linear evolutionary model. This suggests that positive selection may be operating on the mitochondrial genome during thymoma development. In summary, numerous noncoding mutations and mitochondrial heteroplasmic shift were detected in type B1 and B2 thymomas, some of which may be functional. Given the paucity of coding mutations observed in this disease entity, other factors such as disruption of the noncoding landscape and tumour\u2010specific\/enriched mitochondrial heteroplasmic shift, may contribute to the development of thymoma. \u00a9 2025 The Author(s).\n                    <jats:italic>The Journal of Pathology<\/jats:italic>\n                    published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.\n                  <\/jats:p>","DOI":"10.1002\/path.6496","type":"journal-article","created":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T02:51:46Z","timestamp":1764903106000},"page":"135-149","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Genome\u2010wide analysis of somatic noncoding mutation patterns and mitochondrial heteroplasmic shift in type\n                    <scp>B1<\/scp>\n                    and\n                    <scp>B2<\/scp>\n                    thymomas"],"prefix":"10.1002","volume":"268","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0520-733X","authenticated-orcid":false,"given":"Kohei","family":"Fujikura","sequence":"first","affiliation":[{"name":"Department of Diagnostic Pathology, Graduate School of Medicine Kobe University  Kobe Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabel","family":"Correa","sequence":"additional","affiliation":[{"name":"Medical School Building, St Mary's Campus, Norfolk Place Imperial College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne","family":"Heck","sequence":"additional","affiliation":[{"name":"Institute of Diabetes Research, Helmholtz Zentrum Munchen  Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaoru","family":"Watanabe","sequence":"additional","affiliation":[{"name":"Department of Computer Science Osaka Electro\u2010Communication University  Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliet","family":"King","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery Guy's and St Thomas\u2019 NHS foundation trust  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"McLean","sequence":"additional","affiliation":[{"name":"Department of Cellular Pathology Guy's and St Thomas\u2019 NHS foundation trust  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan","family":"Ndagire","sequence":"additional","affiliation":[{"name":"King's Health Partners Cancer Biobank Cancer Centre at Guy's, Guy's and St Thomas\u2019 NHS Foundation Trust  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshihisa","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathology, Graduate School of Medicine Tokyo Medical University  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7052-4289","authenticated-orcid":false,"given":"Masahiko","family":"Kuroda","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathology, Graduate School of Medicine Tokyo Medical University  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Bille","sequence":"additional","affiliation":[{"name":"Department of Cellular Pathology Guy's and St Thomas\u2019 NHS foundation trust  London UK"},{"name":"Cancer Centre, School of Cancer and Pharmaceutical Sciences King's College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daisuke","family":"Nonaka","sequence":"additional","affiliation":[{"name":"Department of Histopathology Guy's and St Thomas\u2019 NHS foundation trust  London UK"},{"name":"Department of Cellular Pathology King's College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,12,4]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2017.11.118"},{"key":"e_1_2_8_3_1","volume-title":"WHO Classification of Tumours of Thoracic Tumours","author":"WHO Classification WHO Classification of Tumours Editorial Board","year":"2021"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2021.10.010"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/his.15097"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1097\/JTO.0000000000000297"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1097\/JTO.0000000000000393"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1288045"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.21037\/med-21-11"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3016"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2018.01.003"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1200\/PO.19.00288"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-017-0424-2"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3101"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3141"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3547"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature22992"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2013.281053"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1097\/PAS.0000000000001155"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2020-321217"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2009.86"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth0410-248"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-016-0994-0"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-1965-x"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2021.102285"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.abg5601"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-023-27675-4"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-023-01561-1"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41525-020-0133-4"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2493-4"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1097\/PAS.0b013e31802b4917"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-1943-3"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1136\/jcp-2022-208655"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.modpat.2022.100008"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1136\/jclinpath-2021-207837"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41379-019-0382-x"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1097\/PAS.0000000000001886"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1111\/his.15024"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-020-0290-x"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms3185"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1002\/path.5988"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb3376"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.14715\/cmb\/2023.69.14.47"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.labinv.2024.102074"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-08136-y"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.12-222711"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-020-03258-3"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gks1205"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2015.454"},{"key":"e_1_2_8_50_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-023-34452-w"},{"key":"e_1_2_8_51_1","doi-asserted-by":"publisher","DOI":"10.1002\/path.6346"},{"key":"e_1_2_8_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.trecan.2022.08.001"},{"key":"e_1_2_8_53_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-019-0557-x"},{"key":"e_1_2_8_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2012.11.053"},{"key":"e_1_2_8_55_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.76.4.1967"},{"key":"e_1_2_8_56_1","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.2012.505"},{"key":"e_1_2_8_57_1","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdz105"},{"key":"e_1_2_8_58_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkr407"},{"key":"e_1_2_8_59_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2014.07.038"},{"key":"e_1_2_8_60_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0139846"},{"key":"e_1_2_8_61_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41576-021-00432-x"},{"key":"e_1_2_8_62_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07368-2"},{"key":"e_1_2_8_63_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-05288-7"},{"key":"e_1_2_8_64_1","doi-asserted-by":"publisher","DOI":"10.1002\/imt2.109"},{"key":"e_1_2_8_65_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-016-0893-4"},{"key":"e_1_2_8_66_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky1015"}],"container-title":["The Journal of Pathology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/path.6496","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/path.6496","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/path.6496","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T11:59:27Z","timestamp":1769774367000},"score":1,"resource":{"primary":{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/10.1002\/path.6496"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,4]]},"references-count":65,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2026,2]]}},"alternative-id":["10.1002\/path.6496"],"URL":"https:\/\/doi.org\/10.1002\/path.6496","archive":["Portico"],"relation":{},"ISSN":["0022-3417","1096-9896"],"issn-type":[{"value":"0022-3417","type":"print"},{"value":"1096-9896","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,4]]},"assertion":[{"value":"2025-08-28","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-10-08","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-04","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}