IDH clonal heterogeneity segregates a subgroup of non‐1p/19q codeleted gliomas with unfavourable clinical outcome

IDH1 胶质瘤 体细胞 生物 医学 遗传异质性 癌症研究 突变 肿瘤科 内科学 遗传学 基因 表型
作者
Shangyi Luo,Shiwei Zhu,Jianlong Liao,Weidong Han,Xiaobo Hou,Tao Luo,Erjie Zhao,Jinyuan Xu,Lin Pang,Xin Liang,Yun Xiao,Xia Li
出处
期刊:Neuropathology and Applied Neurobiology [Wiley]
卷期号:47 (3): 394-405 被引量:6
标识
DOI:10.1111/nan.12671
摘要

Abstract Aims Diffuse gliomas (DGs) are classified into three major molecular subgroups following the revised World Health Organisation (WHO) classification criteria based on their IDH mutation and 1p/19q codeletion status. However, substantial biological heterogeneity and differences in the clinical course are apparent within each subgroup, which remain to be resolved. We sought to assess the clonal status of somatic mutations and explore whether additional molecular subgroups exist within DG. Methods A computational framework that integrates the variant allele frequency, local copy number and tumour purity was used to infer the clonality of somatic mutations in 876 DGs from The Cancer Genome Atlas (TCGA). We performed an unsupervised cluster analysis to identify molecular subgroups and characterised their clinical and biological significance. Results DGs showed widespread genetic intratumoural heterogeneity (ITH), with nearly all driver genes harbouring subclonal mutations, even for known glioma initiating event IDH1 (17.1%). Gliomas with subclonal IDH mutation and without 1p/19q codeletion showed shorter overall and disease‐specific survival, higher ITH and exhibited differences in genomic patterns, transcript levels and proliferative potential, when compared with IDH clonal mutation and no 1p/19q codeletion gliomas. We defined a refined stratification system based on the current WHO glioma molecular classification, which showed close correlations with patients’ clinical outcomes. Conclusions For the first time, we integrated the clonal status of somatic mutations into cancer genomic classification and highlighted the necessity of considering IDH clonal architectures in glioma precision stratification.
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