Upregulated expression of DDR2 and MYLK correlates with poor prognosis in colorectal tumours

Abstract

Background

Optimal response to conventional treatment strategies in treating colorectal cancer (CRC) is not attained in a substantial proportion of patients. This leads to unnecessary side effects, higher risk of recurrence ultimately leading to a poor 5-year survival. Instead, targeting upregulated genes with known functions in tumour progression/recurrence with approved drugs may be a superior alternate to minimize the risk of progression. We therefore performed global gene expression in tumours with CRC, identified upregulated genes, shortlisted and replicated 3 genes with approved drugs in an independent cohort.

Materials and methods

A total of 123 tumours with colorectal cancer were collected in RNALater from patients undergoing treatment primarily by surgery after obtaining written informed consent. RNA was isolated (Qiagen RNAeasy), assessed for quality and transcriptome sequencing (N = 20) performed on Illumina HiSeqX. Data were analysed using The Galaxy platform and dysregulated genes identified. Approved drugs for the upregulated genes were retrieved from The Drug Gene Interaction Database. Relative gene expression of top three upregulated genes (DDR2, AXL and MYLK) were replicated in an independent tumour cohort (N = 103). Control tissues (N = 5) were collected from patients undergoing surgery for reasons other than malignancy.

Results

The mean age of the study group was 54.98 ± 11.80 years that predominantly (75.67 %) comprised of males. Most of the tumours were in the ascending colon (30.10 %) or in rectosigmoid (29.13 %), moderately differentiated adenocarcinomas (77.67 %) in the 2 A stage (46.60 %) or 3B stage (41.75 %). While, 24/103 (23.30 %) tumours showed upregulation of DDR2, 18 (17.47 %) and 16 (15.53 %) tumours showed upregulation of AXL and MYLK genes respectively. Upregulation of DDR2 and MYLK genes were associated with presence of tumour deposits (OR– 4.86; 95 % CI: 1.83–12.94; p = 0.001 and OR– 2.73; 95 % CI: 0.87–8.55; p = 0.08 respectively).

Conclusion

We demonstrate the upregulation of DDR2 and MYLK genes in a sizeable proportion of tumours that were associated with tumour deposits. Tumour deposits are associated with poor prognosis and therefore targeting the tumours with specific approved drugs might reduce the risk of progression and benefit the patient.