P1.28 Dusp4 Expression as A Marker of Heterogeneous Signaling in Colorectal Cancer Patients

Abstract

ABSTRACT Introduction Previous analysis of the gene expression data of mutational subgroups in the PETACC3 trial, revealed a very homogenous gene expression pattern in BRAF mutant CRC patients; while KRAS mutant CRC contain at least three different patient groups in terms of gene expression. One of these KRAS mutant groups together with 10% of KRAS/BRAF WT (WT2) patients, resembled the gene expression found in the BRAF mutants. This BRAF-like subgroup is characterized by poor prognosis. In this article we investigate, if heterogeneity in CRC patients can be partly explained by diverse signaling downstream of KRAS, to which the DUSPs take part. Material and methods The expression of DUSP1, DUSP4 and DUSP6, DUSPs previously shown to be induced by mutations in genes of the MAPK pathway, was analyzed in 4 different CRC patient microarray datasets (PETACC3, cetuximab, TCGA and Agendia dataset). We investigated, if patients with low and high DUSP expression behave differently in terms of response, OS, PFS and differ in clinical characteristics both in PETACC3 and TCGA dataset. Findings Unlike DUSP1, DUSP4 and DUSP6 were differentially overexpressed between BRAF mutants and KRAS mutants on one side and between BRAF mutants and WT2 patients on the other side. When we subdivided the patients into low and high DUSP expression within KRAS mutant and WT2 patients, we found a significant difference in OS in both mutational subgroups with high DUSP4 expression in KRAS mutants associated with a better OS and in WT2 associated with a worse OS. Multivariate analysis in the BRAF WT patients in both PETACC3 and cetuximab dataset showed that high DUSP4 expression was still associated with a worse OS (HR = 1.23; p Conclusions DUSP4 is predictive for OS in CRC patients with KRAS mutations. Interestingly, within KRAS mutant and WT2 patients high DUSP4 expression correlates with clinical characteristics that are typical for BRAF mutant CRC patients. If DUSP4 may represent a novel biomarker for a subset of CRC patients needs further research. Download : Download full-size image Fig. 1 . Box plots with DUSP4 expression according to different mutational groups in PETACC3 dataset. Download : Download full-size image Fig. 2 . Kaplan-Meier curve for overall survival according to DUSP4 expression (low and high) in KRAS WT patients.