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

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...

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Autores principales: Menyhart, Otília, Kakisaka, Tatsuhiko, Pongor, Lőrinc Sándor, Uetake, Hiroyuki, Goel, Ajay, Győrffy, Balázs
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6679198/
https://www.ncbi.nlm.nih.gov/pubmed/31337155
http://dx.doi.org/10.3390/cancers11070983
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author Menyhart, Otília
Kakisaka, Tatsuhiko
Pongor, Lőrinc Sándor
Uetake, Hiroyuki
Goel, Ajay
Győrffy, Balázs
author_facet Menyhart, Otília
Kakisaka, Tatsuhiko
Pongor, Lőrinc Sándor
Uetake, Hiroyuki
Goel, Ajay
Győrffy, Balázs
author_sort Menyhart, Otília
collection PubMed
description 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.
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spelling pubmed-66791982019-08-19 Uncovering Potential Therapeutic Targets in Colorectal Cancer by Deciphering Mutational Status and Expression of Druggable Oncogenes Menyhart, Otília Kakisaka, Tatsuhiko Pongor, Lőrinc Sándor Uetake, Hiroyuki Goel, Ajay Győrffy, Balázs Cancers (Basel) Article 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. MDPI 2019-07-14 /pmc/articles/PMC6679198/ /pubmed/31337155 http://dx.doi.org/10.3390/cancers11070983 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Menyhart, Otília
Kakisaka, Tatsuhiko
Pongor, Lőrinc Sándor
Uetake, Hiroyuki
Goel, Ajay
Győrffy, Balázs
Uncovering Potential Therapeutic Targets in Colorectal Cancer by Deciphering Mutational Status and Expression of Druggable Oncogenes
title Uncovering Potential Therapeutic Targets in Colorectal Cancer by Deciphering Mutational Status and Expression of Druggable Oncogenes
title_full Uncovering Potential Therapeutic Targets in Colorectal Cancer by Deciphering Mutational Status and Expression of Druggable Oncogenes
title_fullStr Uncovering Potential Therapeutic Targets in Colorectal Cancer by Deciphering Mutational Status and Expression of Druggable Oncogenes
title_full_unstemmed Uncovering Potential Therapeutic Targets in Colorectal Cancer by Deciphering Mutational Status and Expression of Druggable Oncogenes
title_short Uncovering Potential Therapeutic Targets in Colorectal Cancer by Deciphering Mutational Status and Expression of Druggable Oncogenes
title_sort uncovering potential therapeutic targets in colorectal cancer by deciphering mutational status and expression of druggable oncogenes
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6679198/
https://www.ncbi.nlm.nih.gov/pubmed/31337155
http://dx.doi.org/10.3390/cancers11070983
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