Faculty, Staff and Student Publications
Publication Date
5-1-2023
Journal
PLOS Computer Biology
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.
Keywords
Humans, Lung Neoplasms, Transcriptome, Adenocarcinoma, Genome-Wide Association Study, Cross-Sectional Studies, Adenocarcinoma of Lung
DOI
10.1371/journal.pcbi.1011122
PMID
37228122
PMCID
PMC10246837
PubMedCentral® Posted Date
5-25-2023
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
