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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doaj-c95c5646cc06402f9b9064778078df632020-11-25T00:45:57ZengMDPI AGCancers2072-66942019-07-0111798310.3390/cancers11070983cancers11070983Uncovering Potential Therapeutic Targets in Colorectal Cancer by Deciphering Mutational Status and Expression of Druggable OncogenesOtília Menyhart0Tatsuhiko Kakisaka1Lőrinc Sándor Pongor2Hiroyuki Uetake3Ajay Goel4Balázs Győrffy52nd Department of Pediatrics, Semmelweis University, Tűzoltó utca 7-9, H-1094 Budapest, HungaryCenter 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, USA2nd Department of Pediatrics, Semmelweis University, Tűzoltó utca 7-9, H-1094 Budapest, HungaryDepartment of Specialized Surgeries, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8519, JapanCenter 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, USA2nd Department of Pediatrics, Semmelweis University, Tűzoltó utca 7-9, H-1094 Budapest, HungaryBackground: 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 <i>DUSP4</i> (<i>p</i> = 2.6 × 10<sup>−12</sup>) in <i>ACVR2A</i> mutated (7.7%) patients; <i>BMP4</i> (<i>p</i> = 1.6 × 10<sup>−04</sup>) in <i>SOX9</i> mutated (8.1%) patients; <i>TRIB2</i> (<i>p</i> = 1.35 × 10<sup>−14</sup>) in <i>ACVR2A</i> mutated patients; <i>VSIG4</i> (<i>p</i> = 2.6 × 10<sup>−05</sup>) in <i>ANK3</i> mutated (7.6%) patients, and <i>DUSP4</i> (<i>p</i> = 7.1 × 10<sup>−04</sup>) in <i>AMER1</i> 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.https://www.mdpi.com/2072-6694/11/7/983colon cancerdisruptive mutationsoncogenesmolecular targeted therapysurvival |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Otília Menyhart Tatsuhiko Kakisaka Lőrinc Sándor Pongor Hiroyuki Uetake Ajay Goel Balázs Győrffy |
spellingShingle |
Otília Menyhart Tatsuhiko Kakisaka Lőrinc Sándor Pongor Hiroyuki Uetake Ajay Goel Balázs Győrffy Uncovering Potential Therapeutic Targets in Colorectal Cancer by Deciphering Mutational Status and Expression of Druggable Oncogenes Cancers colon cancer disruptive mutations oncogenes molecular targeted therapy survival |
author_facet |
Otília Menyhart Tatsuhiko Kakisaka Lőrinc Sándor Pongor Hiroyuki Uetake Ajay Goel Balázs Győrffy |
author_sort |
Otília Menyhart |
title |
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_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_sort |
uncovering potential therapeutic targets in colorectal cancer by deciphering mutational status and expression of druggable oncogenes |
publisher |
MDPI AG |
series |
Cancers |
issn |
2072-6694 |
publishDate |
2019-07-01 |
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 <i>DUSP4</i> (<i>p</i> = 2.6 × 10<sup>−12</sup>) in <i>ACVR2A</i> mutated (7.7%) patients; <i>BMP4</i> (<i>p</i> = 1.6 × 10<sup>−04</sup>) in <i>SOX9</i> mutated (8.1%) patients; <i>TRIB2</i> (<i>p</i> = 1.35 × 10<sup>−14</sup>) in <i>ACVR2A</i> mutated patients; <i>VSIG4</i> (<i>p</i> = 2.6 × 10<sup>−05</sup>) in <i>ANK3</i> mutated (7.6%) patients, and <i>DUSP4</i> (<i>p</i> = 7.1 × 10<sup>−04</sup>) in <i>AMER1</i> 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. |
topic |
colon cancer disruptive mutations oncogenes molecular targeted therapy survival |
url |
https://www.mdpi.com/2072-6694/11/7/983 |
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