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성균관대학교 의과대학, 삼성의료원

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Sci. Transl. Med., Oct 04 2023, 15 (716) | https://doi.org/10.1126/scitranslmed.adh4181 Identifying predictors of glioma evolution from longitudinal sequencing.

Quanhua Mu ^1,2†, Ruichao Chai ^1,3,4†, Bo Pang ^3,4, Yingxi Yang ¹, Hanjie Liu ^3,4, Zheng Zhao^1,3,4, Zhaoshi Bao^1,3,4, Dong Song ¹, Zhihan Zhu ¹, Mengli Yan ¹, Biaobin Jiang ¹, Zongchao Mo ¹, Jihong Tang ¹, Jason K Sa ^5,6, Hee Jin Cho ⁵, Yuzhou Chang 3,4, Kaitlin Hao Yi Chan 1, Danson Shek Chun Loi 1, Sindy Sing Ting Tam 1, Aden Ka Yin Chan 7, Angela Ruohao Wu ¹, Zhaoqi Liu ⁸, Wai Sang Poon ⁹, Ho Keung Ng ⁷, Danny Tat Ming Chan ⁹, Antonio Iavarone ^10*, Do-Hyun Nam ^5,11,12,13*, Tao Jiang ^3,4,13,14*, Jiguang Wang^1,2,13,15*

¹Department of Chemical and Biological Engineering, Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Hong Kong, SAR 999077, China.

²SIAT-HKUST Joint Laboratory of Cell Evolution and Digital Health, Shenzhen-Hong Kong Collaborative Innovation Research Institute, Futian, Shenzhen, Guangdong 518045, China.

³Beijing Neurosurgical Institute, Capital Medical University, Beijing 100070, China.

⁴Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China.

⁵Institute for Refractory Cancer Research, Samsung Medical Center, Seoul 06351, Korea.

⁶Department of Biomedical Sciences, Korea University College of Medicine, Seoul 02841, Korea.

⁷Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong, SAR 999077, China.

⁸CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing 100101, China.

⁹CUHK Otto Wong Brain Tumour Centre, Department of Surgery, Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong SAR 999077, China.

¹⁰Department of Neurological Surgery, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA.

¹¹Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 110745, Korea.

¹²Department of Health Science and Technology, Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University School of Medicine, Seoul 110745, Korea.

¹³Chinese Glioma Genome Atlas (CGGA) and Asian Glioma Genome Atlas (AGGA) Research Networks.

¹⁴Research Unit of Accurate Diagnosis, Treatment, and Translational Medicine of Brain Tumors, Chinese Academy of Medical Sciences, Beijing 100070, China.

¹⁵Hong Kong Center for Neurodegenerative Diseases, InnoHK, Hong Kong, SAR 999077, China.

^*Corresponding authors: Antonio Iavarone, Do-Hyun Nam, Tao Jiang, Jiguang Wang

^†These authors contributed equally to this work.

Abstract

Clonal evolution drives cancer progression and therapeutic resistance. Recent studies have revealed divergent longitudinal trajectories in gliomas, but early molecular features steering posttreatment cancer evolution remain unclear. Here, we collected sequencing and clinical data of initial-recurrent tumor pairs from 544 adult diffuse gliomas and performed multivariate analysis to identify early molecular predictors of tumor evolution in three diffuse glioma subtypes. We found that CDKN2A deletion at initial diagnosis preceded tumor necrosis and microvascular proliferation that occur at later stages of IDH-mutant glioma. Ki67 expression at diagnosis was positively correlated with acquiring hypermutation at recurrence in the IDH-wild-type glioma. In all glioma subtypes, MYC gain or MYC-target activation at diagnosis was associated with treatment-induced hypermutation at recurrence. To predict glioma evolution, we constructed CELLO2 (Cancer EvoLution for LOngitudinal data version 2), a machine learning model integrating features at diagnosis to forecast hypermutation and progression after treatment. CELLO2 successfully stratified patients into subgroups with distinct prognoses and identified a high-risk patient group featured by MYC gain with worse post-progression survival, from the low-grade IDH-mutant-noncodel subtype. We then performed chronic temozolomide-induction experiments in glioma cell lines and isogenic patient-derived gliomaspheres and demonstrated that MYC drives temozolomide resistance by promoting hypermutation. Mechanistically, we demonstrated that, by binding to open chromatin and transcriptionally active genomic regions, c-MYC increases the vulnerability of key mismatch repair genes to treatment-induced mutagenesis, thus triggering hypermutation. This study reveals early predictors of cancer evolution under therapy and provides a resource for precision oncology targeting cancer dynamics in diffuse gliomas.

논문정보

형식Research article
게재일2023년 10월 (BRIC 등록일 2023-10-13)
연구진국내(교신)+국외 연구진
분야 의약학 > 종양의학

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