A SMAD4-modulated gene profile predicts disease-free survival in stage II and III colorectal cancer Journal Article
| Authors: | Szeglin, B. C.; Wu, C.; Marco, M. R.; Park, H. S.; Zhang, Z.; Zhang, B.; Garcia-Aguilar, J.; Beauchamp, R. D.; Chen, X. S.; Smith, J. J. |
| Article Title: | A SMAD4-modulated gene profile predicts disease-free survival in stage II and III colorectal cancer |
| Abstract: | Background: Colorectal cancer is the second-leading cause of cancer-related mortality in the United States and a leading cause of cancer-related mortality worldwide. Loss of SMAD4, a critical tumor suppressor and the central node of the transforming growth factor-beta superfamily, is associated with worse outcomes for colorectal cancer patients; however, it is unknown whether an RNA-based profile associated with SMAD4 expression could be used to better identify high-risk colorectal cancer patients. Aim: Identify a gene expression-based SMAD4-modulated profile and test its association with patient outcome. Methods and results: Using a discovery dataset of 250 colorectal cancer patients, we analyzed expression of BMP/Wnt target genes for association with SMAD4 expression. Promoters of the BMP/Wnt genes were interrogated for SMAD-binding elements. Fifteen genes were implicated and three tested for modulation by SMAD4 in patient-derived colorectal cancer tumoroids. Expression of the 15 genes was used for unsupervised hierarchical clustering of a training dataset and two resulting clusters modeled in a centroid model. This model was applied to an independent validation dataset of stage II and III patients. Disease-free survival was analyzed by the Kaplan-Meier method. In vitro analysis of three genes identified in the SMAD4-modulated profile (JAG1, TCF7, and MYC) revealed modulation by SMAD4 consistent with the trend observed in the profile. In the training dataset (n = 553), the profile was not associated with outcome. However, among stage II and III patients (n = 461), distinct clusters were identified by unsupervised hierarchical clustering that were associated with disease-free survival (p =.02, log-rank test). The main model was applied to a validation dataset of stage II/III CRC patients (n = 257) which confirmed the association of clustering with disease-free survival (p =.013, log-rank test). Conclusions: A SMAD4-modulated gene expression profile identified high-risk stage II and III colorectal cancer patients, can predict disease-free survival, and has prognostic potential for stage II and III colorectal cancer patients. © 2021 The Authors. Cancer Reports published by Wiley Periodicals LLC. |
| Journal Title: | Cancer Reports |
| Volume: | 5 |
| Issue: | 1 |
| ISSN: | 2573-8348 |
| Publisher: | Wiley Periodicals LLC |
| Date Published: | 2022-01-01 |
| Start Page: | e1423 |
| Language: | English |
| DOI: | 10.1002/cnr2.1423 |
| PUBMED: | 34114372 |
| PROVIDER: | scopus |
| PMCID: | PMC8789617 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 March 2022 -- Source: Scopus |
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