Uncovering potential therapeutic targets in colorectal cancer by deciphering mutational status and expression of druggable oncogenes

Otília Menyhart, Tatsuhiko Kakisaka, Lőrinc Sándor Pongor, Hiroyuki Uetake, Ajay Goel, B. Györffy

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article number983
JournalCancers
Volume11
Issue number7
DOIs
Publication statusPublished - Jul 1 2019

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Oncogenes
Colorectal Neoplasms
Mutation
Genes
Therapeutics
Gene Expression
Survival
Survival Analysis
Recurrence

Keywords

  • Colon cancer
  • Disruptive mutations
  • Molecular targeted therapy
  • Oncogenes
  • Survival

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

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; Györffy, B.

In: Cancers, Vol. 11, No. 7, 983, 01.07.2019.

Research output: Contribution to journalArticle

Menyhart, Otília ; Kakisaka, Tatsuhiko ; Pongor, Lőrinc Sándor ; Uetake, Hiroyuki ; Goel, Ajay ; Györffy, B. / Uncovering potential therapeutic targets in colorectal cancer by deciphering mutational status and expression of druggable oncogenes. In: Cancers. 2019 ; Vol. 11, No. 7.
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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.",
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AU - Kakisaka, Tatsuhiko

AU - Pongor, Lőrinc Sándor

AU - Uetake, Hiroyuki

AU - Goel, Ajay

AU - Györffy, B.

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AB - 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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KW - Disruptive mutations

KW - Molecular targeted therapy

KW - Oncogenes

KW - Survival

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