Differential gene expression signatures between colorectal cancers with and without KRAS mutations: crosstalk between the KRAS pathway and other signalling pathways

Abstract

Purpose: KRAS mutation is an important predictive marker in determining resistance to anti-Epidermal Growth Factor Receptor (EGFR) antibody therapies. In order to clarify whether not only KRAS related signalling pathways but also other signalling pathways are altered in patients with colorectal cancers (CRCs) with KRAS mutations, we examined the differences in the gene expression signatures between CRCs with and without KRAS mutation.

Patients and methods: One-hundred and thirteen patients who underwent a surgical resection of a primary CRC were examined. KRAS mutational status was determined using the Peptide Nucleic Acid (PNA)-clamp real-time polymerase chain reaction (PCR) TaqMan assay. Gene expression profiles were compared between CRCs with and without KRAS mutation using the Human Genome GeneChip array U133.

Results: Among 113 CRCs, KRAS mutations were present in 35 tumours (31%). We identified 30 genes (probes) that were differentially expressed between CRCs with and without KRAS mutation (False Discovery Rate (FDR), p<0.01), by which we were able to predict the KRAS status with an accuracy of 90.3%. Thirty discriminating genes included TC21, paired-like homeodomain 1 (PITX1), Sprouty-2, dickkopf homologue 4 (DKK-4), SET and MYND domain containing 3 (SMYD3), mitogen-activated protein kinase kinase kinase 14 (MAP3K14) and c-mer Proto-oncogene tyrosine kinase (MerTK). These genes were related to not only KRAS related signalling pathway but also to other signalling pathways, such as the Wnt-signalling pathway, the NF-kappa B activation pathway and the TGF-beta signalling pathway.

Conclusions: KRAS mutant CRCs exhibited a distinct gene expression signature different from wild-type KRAS CRCs. Using human CRC samples, we were able to show that there is crosstalk between the KRAS-mediated pathway and other signalling pathways. These results are necessary to be taken into account in establishing chemotherapeutic strategies for patients with anti-EGFR-refractory KRAS mutant CRCs.