Hypermutagenesis in untreated adult gliomas due to inherited mismatch mutations

Jason K. Sa, Seung Won Choi, Junfei Zhao, Yeri Lee, Jing Zhang, Doo Sik Kong, Jung Won Choi, Ho Jun Seol, Jung Il Lee, Antonio Iavarone, Raul Rabadan, Do Hyun Nam

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)

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 (pMGMT) 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.

Original languageEnglish
Pages (from-to)3023-3030
Number of pages8
JournalInternational Journal of Cancer
Volume144
Issue number12
DOIs
Publication statusPublished - 2019 Jun 15
Externally publishedYes

Keywords

  • glioma
  • hypermutation
  • mismatch repair deficiency
  • neoantigenicity
  • temozolomide

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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