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Updated: Jan 21, 2026

Orthotopic Mouse Model of Colorectal Cancer
Published on: December 4, 2007
Uncovering Potential Therapeutic Targets in Colorectal Cancer by Deciphering Mutational Status and Expression of
Otília Menyhart1,2, Tatsuhiko Kakisaka3,4, Lőrinc Sándor Pongor1,2
12nd Department of Pediatrics, Semmelweis University, Tűzoltó utca 7-9, H-1094 Budapest, Hungary.
Background:
Numerous driver mutations have been identified in colorectal cancer (CRC), but their relevance to the development of targeted therapies remains elusive. The secondary effects of pathogenic driver mutations on downstream signaling pathways offer a potential approach for the identification of therapeutic targets. We aimed to identify differentially expressed genes as potential drug targets linked to driver mutations.
Methods:
Somatic mutations and the gene expression data of 582 CRC patients were utilized, incorporating the mutational status of 39,916 and the expression levels of 20,500 genes. To uncover candidate targets, the expression levels of various genes in wild-type and mutant cases for the most frequent disruptive mutations were compared with a Mann-Whitney test. A survival analysis was performed in 2100 patients with transcriptomic gene expression data. Up-regulated genes associated with worse survival were filtered for potentially actionable targets. The most significant hits were validated in an independent set of 171 CRC patients.
Results:
Altogether, 426 disruptive mutation-associated upregulated genes were identified. Among these, 95 were linked to worse recurrence-free survival (RFS). Based on the druggability filter, 37 potentially actionable targets were revealed. We selected seven genes and validated their expression in 171 patient specimens. The best independently validated combinations were DUSP4 (p = 2.6 × 10-12) in ACVR2A mutated (7.7%) patients; BMP4 (p = 1.6 × 10-04) in SOX9 mutated (8.1%) patients; TRIB2 (p = 1.35 × 10-14) in ACVR2A mutated patients; VSIG4 (p = 2.6 × 10-05) in ANK3 mutated (7.6%) patients, and DUSP4 (p = 7.1 × 10-04) in AMER1 mutated (8.2%) patients.
Conclusions:
The results uncovered potentially druggable genes in colorectal cancer. The identified mutations could enable future patient stratification for targeted therapy.
Insights
This study identified 37 potentially druggable genes in colorectal cancer (CRC) by analyzing mutation-associated gene expression. These findings may help stratify patients for targeted therapies and improve CRC treatment outcomes.
Area of Science:
- Genomics
- Oncology
- Translational Medicine
Background:
- Colorectal cancer (CRC) has numerous driver mutations, but their therapeutic relevance is unclear.
- Investigating downstream signaling pathway effects of driver mutations can reveal therapeutic targets.
- This study aimed to identify differentially expressed genes linked to driver mutations as potential drug targets.
Purpose of the Study:
- To identify potentially actionable drug targets in colorectal cancer.
- To correlate gene expression changes with specific driver mutations in CRC.
- To discover genes associated with patient survival outcomes in CRC.
Main Methods:
- Somatic mutation and gene expression data from 582 CRC patients were analyzed.
- Gene expression levels in wild-type versus mutant cases were compared using the Mann-Whitney test.
- Survival analysis and druggability filters were applied to identify and validate potential therapeutic targets.
Main Results:
- 426 disruptive mutation-associated upregulated genes were identified in CRC.
- 95 of these genes correlated with worse recurrence-free survival (RFS).
- 37 potentially actionable targets were revealed, with specific genes like DUSP4, BMP4, TRIB2, and VSIG4 validated in patient specimens.
Conclusions:
- Potentially druggable genes were identified in colorectal cancer.
- The identified mutations and associated genes can facilitate future patient stratification for targeted therapy.
- This research provides a foundation for developing novel targeted treatments for CRC.
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