Prognostic value of 5-microRNA based signature in T2-T3N0 colon cancer

Abstract

The role of adjuvant chemotherapy in stage T2-T3N0 colon cancer (CC) is controversial and there are currently no reliable factors allowing for individual selection of patients with high risk of relapse for such therapy. We searched for microRNA-based signature with prognostic significance in this group. We assessed by qRT-PCR expression of 754 microRNAs (miRNAs) in tumour samples from 85 stage pT2-3N0 CC patients treated with surgery alone. MiRNA expression was compared between two groups of patients: 40 and 45 patients who did and did not develop distant metastases after resection, respectively. Additionally, miRNA expression was compared between CC and normal colon mucosa samples and between the mismatch repair (MMR) competent and deficient tumours. Low expression of miR-1300 and miR-939 was significantly correlated with shorter distant metastasis-free survival (DMFS) in Cox univariate analysis (p.adjusted = 0.049). The expression signature of five miRNAs (miR-1296, miR-135b, miR-539, miR-572 and miR-185) was found to be prognostic [p = 1.28E-07, HR 8.4 (95 % CI: 3.81-18.52)] for DMFS and cross-validated in a leave-one-out analysis, with the sensitivity and specificity of 74 and 78 %, respectively. The expression of miR-592 was significantly associated with the MMR status (p.adjusted <0.01). The expression of several novel miRNAs were found to be tumour specific, e.g. miR-888, miR-523, miR-18b, miR-302a, miR-423-5p, miR-582-3p (p < 0.05). We developed a miRNA expression signature that may be predictive for the risk of distant relapse in early stage CC and confirmed previously reported association between miR-592 expression and MMR status.

Keywords: colon cancer; metastasis; miR-1300; miR-939; microRNA expression; prognostic marker.

Fig. 1

Metastasis-free survival according to the 5-miRNA expression signature (RS threshold = 0.5) (a) and the area under the curve for estimating 3 year metastasis-free survival using the 5-miRNA expression signature (b)

Fig. 2

Results of hierarchical clustering of average expression data for miRNAs constituting the 5-miRNA prognostic signature in two independent experiments: the original data set and GSE63119 data set. Expression values measured in two different platforms were integrated using the z-score transformation. The clustering was performed on average signal from ‘relapsed’ and ‘non-relapsed’ samples in both experiments with Euclidean distance metric

Fig. 3

Expression of miR-888 and miR-1243 in normal colon mucosa (NCM) and in colon cancer (CC)