{"doi":"10.1101/2020.02.16.20023663","title":"A SMAD4-modulated gene profile predicts disease-free survival in stage II and III colorectal cancer","abstract":"Abstract Objective Loss of SMAD4 is associated with worse outcomes for colorectal cancer patients. We used gene ontology and bioinformatics to identify an RNA-based SMAD4-modulated profile and test its association with patient outcome. Design 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. 15 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. Results In vitro analysis of three genes identified in the SMAD4-modulated profile (JAG1, TCF7, 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 = 0.02). The main model was applied to a validation dataset (n = 257) which confirmed the association of clustering with disease-free survival (p = 0.02). Conclusions A SMAD4-modulated RNA-based gene 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.","journal":"medRxiv","year":2020,"id":123517,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9592,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":238282,"name":"Chao Wu","orcid":"0000-0003-0260-2868","position":1,"is_corresponding":false},{"id":566405,"name":"Michael R. Marco","orcid":"0000-0001-6731-0810","position":2,"is_corresponding":false},{"id":566406,"name":"Hyun Sung Park","orcid":"0000-0002-0526-3593","position":3,"is_corresponding":false},{"id":238279,"name":"Zeda Zhang","orcid":"0000-0002-7225-534X","position":4,"is_corresponding":false},{"id":7638,"name":"Bing Zhang","orcid":"0000-0001-8676-2425","position":5,"is_corresponding":false},{"id":239558,"name":"Julio García‐Aguilar","orcid":"0000-0003-2451-0948","position":6,"is_corresponding":false},{"id":566407,"name":"R. Daniel Beauchamp","orcid":"0000-0002-8446-4114","position":7,"is_corresponding":false},{"id":291504,"name":"Xi Chen","orcid":"0000-0002-8609-5391","position":8,"is_corresponding":false},{"id":239559,"name":"J. Joshua Smith","orcid":"0000-0003-2538-5456","position":9,"is_corresponding":false},{"id":239548,"name":"Bryan Szeglin","orcid":"0000-0002-7866-7548","position":0,"is_corresponding":true}],"reference_count":52,"raw_metadata":null,"created_at":"2026-07-18T23:14:59.547352Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}