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 B细胞 抗体
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,Angela Ruohao Wu,Zhaoqi Liu,Wai Sang Poon,Ho‐Keung Ng,Danny Tat Ming Chan,Antonio Iavarone,Do‐Hyun Nam,Tao Jiang,Jiguang Wang
出处
期刊:Science Translational Medicine [American Association for the Advancement of Science (AAAS)]
卷期号:15 (716) 被引量:9
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.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
dildil发布了新的文献求助10
1秒前
1秒前
2秒前
2秒前
边瑞明完成签到,获得积分10
2秒前
Wang发布了新的文献求助10
3秒前
Jenny应助拼搏思卉采纳,获得10
3秒前
3秒前
神勇的雅香应助不喝可乐采纳,获得10
3秒前
清脆的白开水完成签到,获得积分10
3秒前
Hello应助善良过客采纳,获得10
3秒前
现实的曼荷完成签到,获得积分10
3秒前
3秒前
4秒前
zyyyy完成签到,获得积分10
4秒前
dd完成签到,获得积分20
4秒前
4秒前
混子发布了新的文献求助10
4秒前
HYG完成签到,获得积分10
5秒前
二橦完成签到 ,获得积分10
5秒前
熊博士完成签到,获得积分10
6秒前
哲000发布了新的文献求助10
6秒前
丰富的世界完成签到 ,获得积分10
6秒前
7秒前
7秒前
路漫漫其修远兮完成签到,获得积分10
7秒前
GGZ发布了新的文献求助10
7秒前
啦啦啦发布了新的文献求助10
7秒前
8秒前
阿坤完成签到,获得积分10
9秒前
dd发布了新的文献求助10
10秒前
桐桐应助小智采纳,获得10
10秒前
九川完成签到,获得积分10
10秒前
混子完成签到,获得积分10
10秒前
10秒前
11秒前
Wang完成签到,获得积分10
11秒前
星辰大海应助Ll采纳,获得10
11秒前
Jasper应助妮儿采纳,获得10
12秒前
tododoto完成签到,获得积分10
12秒前
高分求助中
Continuum Thermodynamics and Material Modelling 3000
Production Logging: Theoretical and Interpretive Elements 2700
Social media impact on athlete mental health: #RealityCheck 1020
Ensartinib (Ensacove) for Non-Small Cell Lung Cancer 1000
Unseen Mendieta: The Unpublished Works of Ana Mendieta 1000
Bacterial collagenases and their clinical applications 800
El viaje de una vida: Memorias de María Lecea 800
热门求助领域 (近24小时)
化学 材料科学 生物 医学 工程类 有机化学 生物化学 物理 纳米技术 计算机科学 内科学 化学工程 复合材料 基因 遗传学 物理化学 催化作用 量子力学 光电子学 冶金
热门帖子
关注 科研通微信公众号,转发送积分 3527699
求助须知:如何正确求助?哪些是违规求助? 3107752
关于积分的说明 9286499
捐赠科研通 2805513
什么是DOI,文献DOI怎么找? 1539954
邀请新用户注册赠送积分活动 716878
科研通“疑难数据库(出版商)”最低求助积分说明 709759