Hypermutagenesis in untreated adult gliomas due to inherited mismatch mutations. Issue 12 (7th January 2019)

• Record Type: Journal Article
• Authors: Sa, Jason K.; Choi, Seung Won; Zhao, Junfei; Lee, Yeri; Zhang, Jing; Kong, Doo‐Sik; Choi, Jung Won; Seol, Ho Jun; Lee, Jung‐Il; Iavarone, Antonio; Rabadan, Raul; Nam, Do‐Hyun
• Is Part Of: International journal of cancer. Volume 144:Issue 12(2019)
• Page Start: 3023
• Page End: 3030
• Publication Date: 2019-01-07
• Subjects: hypermutation -- temozolomide -- neoantigenicity -- glioma -- mismatch repair deficiency; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.32054
• Languages: English
• ISSNs: 0020-7136

Abstract

Abstract : Hypermutagenesis refers to marked increase in the number of mutations due to continuous mutagenic process. 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)‐induced mutagenesis. In our study, we have identified a rare subset of treatment‐naïve adult gliomas with de novo hypermutator phenotype and explored the evolution of spontaneous and treatment‐induced hypermutagenesis. We conducted Whole‐Exome Sequencing (WES), Whole‐Transcriptome Sequencing (WTS), and Single‐Cell Sequencing (SCS) of TMZ‐naïve and post‐TMZ‐treated hypermutated tumors to identify distinct clinical or genomic manifestations that contribute to the development of hypermutation in untreated adult gliomas. TMZ‐naïve hypermutated tumors were marked by absence of IDH1 somatic mutation and MGMT promoter (p MGMT ) methylation, two genomic traits that were significantly associated with the TMZ‐induced hypermutagenic event in glioblastoma, and harbored inherited alterations in the mismatch repair (MMR) machinery. The immediate family members of the TMZ‐naive 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‐naïve and post‐TMZ‐treated 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. Abstract : What's new? Hypermutation has been observed in a subset of adult glioma patients as a direct result of temozolomide (TMZ)‐induced mutagenesis, leading to therapeutic resistance. Here, the authors identified a rare subset of pre‐treatment adult glioma patients with de novo hypermutator phenotype. TMZ‐naïve hypermutated tumors lacked somatic mutation of IDH1 and MGMT promoter methylation, and harbored both germline and somatic dysregulation of mismatch repair machinery encoding genes. Patients with TMZ‐naïve hypermutagenesis demonstrated high incidence of cancer‐development history in their immediate family members. Both TMZ‐naïve and post‐TMZ treated hypermutated tumors exhibited a significant accumulatin of neoantigen loads, pointing towards potential implementation of immunotherapy.