Clinical Significance and Molecular Annotation of Cellular Morphometric Subtypes in Lower Grade Gliomas discovered by Machine Learning
Liu, Xiao-Ping; Jin, Xiaoqing; Ahmadian, Saman Seyed; Yang, Xu; Tian, Su-Fang; Cai, Yu-Xiang; Chawla, Kuldeep; Snijders, Antoine M; Xia, Yankai; van Diest, Paul J; Weiss, William A; Mao, Jian-Hua; Li, Zhi-Qiang; Vogel, Hannes; Chang, Hang
(2023) Neuro-oncology, volume 25, issue 1, pp. 68 - 81
(Article)
Abstract
BACKGROUND: Lower-grade gliomas (LGG) are heterogeneous diseases by clinical, histological, and molecular criteria. We aimed to personalize the diagnosis and therapy of LGG patients by developing and validating robust cellular morphometric subtypes (CMS) and to uncover the molecular signatures underlying these subtypes. METHODS: Cellular morphometric biomarkers (CMBs) were identified with
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artificial intelligence technique from TCGA-LGG cohort. Consensus clustering was used to define CMS. Survival analysis was performed to assess the clinical impact of CMBs and CMS. A nomogram was constructed to predict 3- and 5-year overall survival (OS) of LGG patients. Tumor mutational burden (TMB) and immune cell infiltration between subtypes were analyzed using the Mann-Whitney U test. The double-blinded validation for important immunotherapy-related biomarkers was executed using immunohistochemistry (IHC). RESULTS: We developed a machine learning (ML) pipeline to extract CMBs from whole-slide images of tissue histology; identifying and externally validating robust CMS of LGGs in multicenter cohorts. The subtypes had independent predicted OS across all three independent cohorts. In the TCGA-LGG cohort, patients within the poor-prognosis subtype responded poorly to primary and follow-up therapies. LGGs within the poor-prognosis subtype were characterized by high mutational burden, high frequencies of copy number alterations, and high levels of tumor-infiltrating lymphocytes and immune checkpoint genes. Higher levels of PD-1/PD-L1/CTLA-4 were confirmed by IHC staining. In addition, the subtypes learned from LGG demonstrate translational impact on glioblastoma (GBM). CONCLUSIONS: We developed and validated a framework (CMS-ML) for CMS discovery in LGG associated with specific molecular alterations, immune microenvironment, prognosis, and treatment response.
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Keywords: Artificial Intelligence, Brain Neoplasms/pathology, Clinical Relevance, Glioma/pathology, Humans, Machine Learning, Tumor Microenvironment, cellular morphometric biomarkers, cellular morphometric subtypes, glioblastoma, lower-grade glioma, overall survival, stacked predictive sparse decomposition, immunohistochemistry, nomogram, Clinical Neurology, Oncology, Cancer Research, Multicenter Study, Journal Article
ISSN: 1522-8517
Publisher: Oxford University Press
Note: Publisher Copyright: © The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
(Peer reviewed)