Identifying predictors of glioma evolution from longitudinal sequencing.

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.

• Authors: Quanhua Mu, Ruichao Chai, Bo Pang, Yingxi Yang, Hanjie Liu, Zheng Zhao, Zhaoshi Bao, Dong Song, Zhihan Zhu, Mengli Yan, Biaobin Jiang, Zongchao Mo, Jihong Tang, Jason K Sa, Hee Jin Cho, Yuzhou Chang, Kaitlin Hao Yi Chan, Danson Shek Chun Loi, Sindy Sing Ting Tam, Aden Ka Yin Chan, Angela Ruohao Wu, Zhaoqi Liu, Wai Sang Poon, Ho Keung Ng, Danny Tat Ming Chan, Antonio Iavarone, Do-Hyun Nam, Tao Jiang, Jiguang Wang
• Journal: Science translational medicine (Sci Transl Med) Vol. 15 Issue 716 Pg. eadh4181 (10 04 2023) ISSN: 1946-6242 [Electronic] United States
• PMID: 37792958 (Publication Type: Journal Article)

Chemical References

• Temozolomide

Topics

• Adult
• Humans
• Brain Neoplasms (therapy)
• Temozolomide (pharmacology, therapeutic use)
• Mutation (genetics)
• Precision Medicine
• Neoplasm Recurrence, Local (drug therapy)
• Glioma (drug therapy)