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 language | English |
---|---|
Pages (from-to) | 3023-3030 |
Number of pages | 8 |
Journal | International Journal of Cancer |
Volume | 144 |
Issue number | 12 |
DOIs | |
Publication status | Published - 2019 Jun 15 |
Externally published | Yes |
Bibliographical note
Funding Information:Key words: hypermutation, temozolomide, neoantigenicity, glioma, mismatch repair deficiency Additional Supporting Information may be found in the online version of this article. J.K.S. and S.W.C. contributed equally to this work. Conflict of interest: The authors declare no competing financial interests. Grant sponsor: Korea Health Technology R&D project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea; Grant number: HI14C3418 DOI: 10.1002/ijc.32054 This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. History: Received 3 Sep 2018; Accepted 29 Nov 2018; Online 11 Dec 2018 Correspondence to: Do-Hyun Nam M.D. Ph.D., Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, Republic of Korea, Tel.: 82-2-3410-3497, E-mail: [email protected]
Funding Information:
The biospecimens for our study were provided by Samsung Medical Center BioBank.
Publisher Copyright:
© 2018 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC
Keywords
- glioma
- hypermutation
- mismatch repair deficiency
- neoantigenicity
- temozolomide
ASJC Scopus subject areas
- Oncology
- Cancer Research