Identifying predictors of glioma evolution from longitudinal sequencing

胶质瘤 体细胞突变 替莫唑胺 生物 癌症的体细胞进化 癌症研究 CDKN2A 肿瘤进展 癌症 肿瘤科 遗传学 医学 抗体 B细胞
作者
Quanhua Mu,Ruichao Chai,Bo Pang,Yingxi Yang,Hanjie Liu,Zheng Zhao,Zhaoshi Bao,Song Dong,Zhi‐Han Zhu,Mengli Yan,Biaobin Jiang,Zongchao Mo,Jihong Tang,K. Jason,Hee Jin Cho,Yuzhou Chang,Kaitlin Hao Yi Chan,Danson Loi,Sindy Sing Ting Tam,Aden Ka‐Yin Chan
出处
期刊:Science Translational Medicine [American Association for the Advancement of Science]
卷期号:15 (716) 被引量:12
标识
DOI:10.1126/scitranslmed.adh4181
摘要

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.
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