{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T22:28:27Z","timestamp":1785796107458,"version":"3.56.0"},"reference-count":36,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2022,12,15]],"date-time":"2022-12-15T00:00:00Z","timestamp":1671062400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32070690"],"award-info":[{"award-number":["32070690"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81830070"],"award-info":[{"award-number":["81830070"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82102512"],"award-info":[{"award-number":["82102512"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molecular Oncology"],"published-print":{"date-parts":[[2023,5]]},"abstract":"<jats:p>Mitochondrial DNA (mtDNA) somatic mutations play important roles in the initiation and progression of cancer. Although next\u2010generation sequencing (NGS) of paired tumor and control samples has become a common practice to identify tumor\u2010specific mtDNA mutations, the unique nature of mtDNA and NGS\u2010associated sequencing bias could cause false\u2010positive\/\u2010negative somatic mutation calling. Additionally, there are clinical scenarios where matched control tissues are unavailable for comparison. Therefore, a novel approach for accurately identifying somatic mtDNA variants is greatly needed, particularly in the absence of matched controls. In this study, the ground truth mtDNA variants orthogonally validated by triple\u2010paired tumor, adjacent nontumor, and blood samples were used to develop mitoSomatic, a random forest\u2010based machine learning tool. We demonstrated that mitoSomatic achieved area under the curve (AUC) values over 0.99 for identifying somatic mtDNA variants without paired control in three tumor types. In addition, mitoSomatic was also applicable in nontumor tissues such as adjacent nontumor and blood samples, suggesting the flexibility of mitoSomatic's classification capability. Furthermore, analysis of triple\u2010paired samples identified a small group of variants with uncertain somatic\/germline origin, whereas application of mitoSomatic significantly facilitated the prediction of their possible source. Finally, a control\u2010free evaluation of the public pan\u2010cancer NGS dataset with mitoSomatic revealed a substantial number of variants that were probably misclassified by conventional tumor\u2010control comparison, further emphasizing the usefulness of mitoSomatic in application. Taken together, our study demonstrates that mitoSomatic is valuable for accurately identifying somatic mtDNA variants in mtDNA NGS data without paired controls, applicable for both tumor and nontumor tissues.<\/jats:p>","DOI":"10.1002\/1878-0261.13335","type":"journal-article","created":{"date-parts":[[2022,11,4]],"date-time":"2022-11-04T09:00:05Z","timestamp":1667552405000},"page":"857-871","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["<scp>mitoSomatic<\/scp>: a tool for accurate identification of mitochondrial <scp>DNA<\/scp> somatic mutations without paired controls"],"prefix":"10.1002","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6484-4777","authenticated-orcid":false,"given":"Wenjie","family":"Guo","sequence":"first","affiliation":[{"name":"State Key Laboratory of Cancer Biology and Department of Physiology and Pathophysiology Fourth Military Medical University  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cancer Biology and Department of Physiology and Pathophysiology Fourth Military Medical University  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liping","family":"Su","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cancer Biology and Department of Physiology and Pathophysiology Fourth Military Medical University  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanshan","family":"Guo","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cancer Biology and Department of Physiology and Pathophysiology Fourth Military Medical University  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fanfan","family":"Xie","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cancer Biology and Department of Physiology and Pathophysiology Fourth Military Medical University  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoying","family":"Ji","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cancer Biology and Department of Physiology and Pathophysiology Fourth Military Medical University  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaixiang","family":"Zhou","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cancer Biology and Department of Physiology and Pathophysiology Fourth Military Medical University  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4902-8859","authenticated-orcid":false,"given":"Xu","family":"Guo","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cancer Biology and Department of Physiology and Pathophysiology Fourth Military Medical University  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9575-5654","authenticated-orcid":false,"given":"Xiwen","family":"Gu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine Fourth Military Medical University  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8979-2056","authenticated-orcid":false,"given":"Jinliang","family":"Xing","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cancer Biology and Department of Physiology and Pathophysiology Fourth Military Medical University  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,12,15]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.07.002"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41576\u2010020\u201000284\u2010x"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrg3966"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588\u2010018\u20100264\u2010z"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.02935"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588\u2010019\u20100557\u2010x"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42255\u2010021\u201000378\u20108"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s43018\u2010020\u201000112\u20105"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1156906"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdz105"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2014.170"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41568\u2010021\u201000358\u2010w"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddx172"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1419651112"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btr629"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12864-016-3281-2"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13059\u2010015\u20100758\u20102"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1093\/bib\/bbaa272"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13073\u2010017\u20100446\u20109"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btv685"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.31395"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtn.2020.11.002"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp352"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.107524.110"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gks1443"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.33927"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtn.2020.12.017"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bth261"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/0471250953.bi0123s44"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/29.1.308"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkq603"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkj010"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkr407"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1005333"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrg3275"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41580\u2010021\u201000407\u20100"}],"container-title":["Molecular Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/1878-0261.13335","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/1878-0261.13335","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/febs.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/1878-0261.13335","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,22]],"date-time":"2023-08-22T00:02:14Z","timestamp":1692662534000},"score":1,"resource":{"primary":{"URL":"https:\/\/febs.onlinelibrary.wiley.com\/doi\/10.1002\/1878-0261.13335"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,15]]},"references-count":36,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2023,5]]}},"alternative-id":["10.1002\/1878-0261.13335"],"URL":"https:\/\/doi.org\/10.1002\/1878-0261.13335","archive":["Portico"],"relation":{},"ISSN":["1574-7891","1878-0261"],"issn-type":[{"value":"1574-7891","type":"print"},{"value":"1878-0261","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,15]]},"assertion":[{"value":"2022-08-11","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-11-03","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-12-15","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}