Inferring evolutionary trajectories from cross-sectional transcriptomic data to mirror lung adenocarcinoma progression
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Published:2023-05-25
Issue:5
Volume:19
Page:e1011122
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ISSN:1553-7358
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Container-title:PLOS Computational Biology
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language:en
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Short-container-title:PLoS Comput Biol
Author:
Huang Kexin,
Zhang Yun,
Gong Haoran,
Qiao Zhengzheng,
Wang Tiangang,
Zhao Weiling,
Huang LiyuORCID,
Zhou Xiaobo
Abstract
Lung adenocarcinoma (LUAD) is a deadly tumor with dynamic evolutionary process. Although much endeavors have been made in identifying the temporal patterns of cancer progression, it remains challenging to infer and interpret the molecular alterations associated with cancer development and progression. To this end, we developed a computational approach to infer the progression trajectory based on cross-sectional transcriptomic data. Analysis of the LUAD data using our approach revealed a linear trajectory with three different branches for malignant progression, and the results showed consistency in three independent cohorts. We used the progression model to elucidate the potential molecular events in LUAD progression. Further analysis showed that overexpression of BUB1B, BUB1 and BUB3 promoted tumor cell proliferation and metastases by disturbing the spindle assembly checkpoint (SAC) in the mitosis. Aberrant mitotic spindle checkpoint signaling appeared to be one of the key factors promoting LUAD progression. We found the inferred cancer trajectory allows to identify LUAD susceptibility genetic variations using genome-wide association analysis. This result shows the opportunity for combining analysis of candidate genetic factors with disease progression. Furthermore, the trajectory showed clear evident mutation accumulation and clonal expansion along with the LUAD progression. Understanding how tumors evolve and identifying mutated genes will help guide cancer management. We investigated the clonal architectures and identified distinct clones and subclones in different LUAD branches. Validation of the model in multiple independent data sets and correlation analysis with clinical results demonstrate that our method is effective and unbiased.
Funder
National Natural Science Foundation of China
National Key Research and Development Program of China
Publisher
Public Library of Science (PLoS)
Subject
Computational Theory and Mathematics,Cellular and Molecular Neuroscience,Genetics,Molecular Biology,Ecology,Modeling and Simulation,Ecology, Evolution, Behavior and Systematics