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Uncovering Potential Therapeutic Targets in Colorectal Cancer by Deciphering Mutational Status and Expression of Druggable Oncogenes

1
2nd Department of Pediatrics, Semmelweis University, Tűzoltó utca 7-9, H-1094 Budapest, Hungary
2
MTA TTK Lendület Cancer Biomarker Research Group, Institute of Enzymology, Hungarian Academy of Sciences, Magyar tudósok körútja 2., H-1117 Budapest, Hungary
3
Center for Gastrointestinal Research & Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, 3410 Worth Street, Suite 610, Dallas, TX 75246, USA
4
Department of Molecular Diagnostics, Therapeutics and Translational Oncology, Beckman Research Institute at City of Hope Comprehensive Cancer Center, 1218 S. Fifth Avenue, Monrovia, Suite 2226, CA 91016, USA
5
Department of Specialized Surgeries, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8519, Japan
*
Authors to whom correspondence should be addressed.
These authors share equal contribution.
Cancers 2019, 11(7), 983; https://doi.org/10.3390/cancers11070983
Received: 20 May 2019 / Revised: 28 June 2019 / Accepted: 11 July 2019 / Published: 14 July 2019
(This article belongs to the Special Issue New Biomarkers in Cancers)
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Abstract

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. View Full-Text
Keywords: colon cancer; disruptive mutations; oncogenes; molecular targeted therapy; survival colon cancer; disruptive mutations; oncogenes; molecular targeted therapy; survival
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Menyhart, O.; Kakisaka, T.; Pongor, L.S.; Uetake, H.; Goel, A.; Győrffy, B. Uncovering Potential Therapeutic Targets in Colorectal Cancer by Deciphering Mutational Status and Expression of Druggable Oncogenes. Cancers 2019, 11, 983.

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