A SMAD4-modulated gene profile predicts disease-free survival in stage II and III colorectal cancer

Bryan C. Szeglin, Chao Wu, Michael R. Marco, Hyun Sung Park, Zeda Zhang, Bing Zhang, Julio Garcia-Aguilar, R. Daniel Beauchamp, X. Steven Chen, J. Joshua Smith

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
JournalCancer Reports
DOIs
StateAccepted/In press - 2021

Keywords

  • SMAD4
  • cancer biology
  • colorectal cancer
  • gene expression profile
  • tumor suppressor genes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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