Independent transcriptional patterns reveal biological processes associated with disease-free survival in early colorectal cancer

• Published in: Communications medicine Vol. 4; no. 1; p. 79
• Main Authors: Knapen, Daan G., Hone Lopez, Sara, de Groot, Derk Jan A., de Haan, Jacco-Juri, de Vries, Elisabeth G. E., Dienstmann, Rodrigo, de Jong, Steven, Bhattacharya, Arkajyoti, Fehrmann, Rudolf S. N.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.05.2024; Springer Nature B.V; Nature Portfolio
• Subjects: 38; 631/67/1504/1885; 631/67/69; Cancer therapies; Colorectal cancer; Datasets; Gene expression; Integrated approach; Large intestine; Medicine; Medicine & Public Health; Patients; Principal components analysis; Regression analysis; Sarcoma; Sensitivity analysis; Survival analysis; Transcription factors
• DOI: 10.1038/s43856-024-00504-z
• ISSN: 2730-664X

Background Bulk transcriptional profiles of early colorectal cancer (CRC) can fail to detect biological processes associated with disease-free survival (DFS) if the transcriptional patterns are subtle and/or obscured by other processes’ patterns. Consensus-independent component analysis (c-ICA) can dissect such transcriptomes into statistically independent transcriptional components (TCs), capturing both pronounced and subtle biological processes. Methods In this study we (1) integrated transcriptomes ( n  = 4228) from multiple early CRC studies, (2) performed c-ICA to define the TC landscape within this integrated data set, 3) determined the biological processes captured by these TCs, (4) performed Cox regression to identify DFS-associated TCs, (5) performed random survival forest (RSF) analyses with activity of DFS-associated TCs as classifiers to identify subgroups of patients, and 6) performed a sensitivity analysis to determine the robustness of our results Results We identify 191 TCs, 43 of which are associated with DFS, revealing transcriptional diversity among DFS-associated biological processes. A prominent example is the epithelial-mesenchymal transition (EMT), for which we identify an association with nine independent DFS-associated TCs, each with coordinated upregulation or downregulation of various sets of genes. Conclusions This finding indicates that early CRC may have nine distinct routes to achieve EMT, each requiring a specific peri-operative treatment strategy. Finally, we stratify patients into DFS patient subgroups with distinct transcriptional patterns associated with stage 2 and stage 3 CRC. Plain language summary While treatments for patients with colorectal cancer have improved, many patients (around 30-50%) have cancers that will eventually relapse and these patients will die due to their disease. Researchers have been studying the genes involved in colorectal cancer to help us understand why some cancers might relapse. However, current methods to do this may miss subtle or hidden patterns in the gene activity related to cancer relapse. To deal with this, we used a special method called consensus-independent component analysis (c-ICA) to dig more deeply into the activity of genes. This helped us to uncover some potential biological processes underpinning colorectal cancer relapse, which ultimately could help researchers to identify better treatments for patients with colorectal cancer. Knapen et al. apply consensus-independent transcriptional component analysis to dissect transcriptomes into statistically independent transcriptional components in early colorectal cancer. Their findings identify 43 biological processes associated with disease-free survival which enables stratification of patients into different subgroups.