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Hypermutated tumors, have being found in several tumor types, are associated with inherited or acquired alterations in the DNA repair pathways. Hypermutation has been observed in a subset of adult glioma patients as a direct result of temozolomide(TMZ)\u2010induced mutagenesis. In our study, we have identified a rare subset of treatment\u2010na\u00efve adult gliomas with <jats:italic>de novo<\/jats:italic> hypermutator phenotype and explored the evolution of spontaneous and treatment\u2010induced hypermutagenesis. We conducted Whole\u2010Exome Sequencing (WES), Whole\u2010Transcriptome Sequencing (WTS), and Single\u2010Cell Sequencing (SCS) of TMZ\u2010na\u00efve and post\u2010TMZ\u2010treated hypermutated tumors to identify distinct clinical or genomic manifestations that contribute to the development of hypermutation in untreated adult gliomas. TMZ\u2010na\u00efve hypermutated tumors were marked by absence of <jats:italic>IDH1<\/jats:italic> somatic mutation and <jats:italic>MGMT<\/jats:italic> promoter (p<jats:italic>MGMT<\/jats:italic>) methylation, two genomic traits that were significantly associated with the TMZ\u2010induced hypermutagenic event in glioblastoma, and harbored inherited alterations in the mismatch repair (MMR) machinery. The immediate family members of the TMZ\u2010naive hypermutated glioma patients were also previous diagnosed with cancer development history, suggesting that germline dysfunction of the MMR pathway could potentially pose hereditary risk to genetic predisposition of carcinogenesis in gliomas. Lastly, both TMZ\u2010na\u00efve and post\u2010TMZ\u2010treated hypermutated tumors exhibited a significant accumulation of neoantigen loads, suggesting immunotherapeutic alternatives. Our results present new and unique understanding of hypermutagenic process in adult gliomas and an important step towards clinical implication of immunotherapy in glioma treatment.<\/jats:p>","DOI":"10.1002\/ijc.32054","type":"journal-article","created":{"date-parts":[[2018,12,11]],"date-time":"2018-12-11T09:24:59Z","timestamp":1544520299000},"page":"3023-3030","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Hypermutagenesis in untreated adult gliomas due to inherited mismatch mutations"],"prefix":"10.1002","volume":"144","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3251-5004","authenticated-orcid":false,"given":"Jason K.","family":"Sa","sequence":"first","affiliation":[{"name":"Institute for Refractory Cancer Research, Samsung Medical Center  Seoul Republic of Korea"},{"name":"Research Institute for Future Medicine, Samsung Medical Center  Seoul Republic of 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