TY - JOUR
T1 - Identifying predictors of glioma evolution from longitudinal sequencing
AU - Mu, Quanhua
AU - Chai, Ruichao
AU - Pang, Bo
AU - Yang, Yingxi
AU - Liu, Hanjie
AU - Zhao, Zheng
AU - Bao, Zhaoshi
AU - Song, Dong
AU - Zhu, Zhihan
AU - Yan, Mengli
AU - Jiang, Biaobin
AU - Mo, Zongchao
AU - Tang, Jihong
AU - Sa, Jason K.
AU - Cho, Hee Jin
AU - Chang, Yuzhou
AU - Chan, Kaitlin Hao Yi
AU - Loi, Danson Shek Chun
AU - Tam, Sindy Sing Ting
AU - Chan, Aden Ka Yin
AU - Wu, Angela Ruohao
AU - Liu, Zhaoqi
AU - Poon, Wai Sang
AU - Ng, Ho Keung
AU - Chan, Danny Tat Ming
AU - Iavarone, Antonio
AU - Nam, Do Hyun
AU - Jiang, Tao
AU - Wang, Jiguang
N1 - Publisher Copyright:
© 2023 The Authors, some rights reserved.
PY - 2023/10/4
Y1 - 2023/10/4
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85175269626&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.adh4181
DO - 10.1126/scitranslmed.adh4181
M3 - Article
C2 - 37792958
AN - SCOPUS:85175269626
SN - 1946-6234
VL - 15
JO - Science Translational Medicine
JF - Science Translational Medicine
IS - 716
M1 - eadh4181
ER -