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.Electronic supplementary materialThe online version of this article (doi:10.1007/s10585-016-9810-1) contains supplementary material, which is available to authorized users.
Highlights
Colon cancer (CC) is the fourth greatest cause of cancerrelated deaths worldwide [1]
The RNA quality was typical of formalin-fixed paraffin-embedded (FFPE) samples and the Ct values for RNAs chosen for normalisation are shown in Appendix A, Table 1 in Supplementary material
By analysing discretised data we found the expression of 30 miRNAs present in primary tumours, e.g. miR-888, miR-523, miR-18b, miR-302a, miR-339-5p, miR-423-5p, miR-582-3p, miR-1243 (p \ 0.05) and the expression of miR-299-5p and miR-1262 specific to normal colon mucosa (NCM) (p \ 0.05) (Fig. 3)
Summary
Colon cancer (CC) is the fourth greatest cause of cancerrelated deaths worldwide [1]. MicroRNAs (miRNAs) are short, non-coding RNAs that play key roles in cancer cell [15] These molecules regulate gene expression by binding to the target sequences of mRNA, which results in hindered translation [16]. Zhang et al [19] demonstrated the prognostic value of 5-miRNA-expression signature in stage II CC, and validated it in sizeable validation cohorts. We explored prognostic value of miRNA expression in stage T2-T3N0 CC, with the aim of developing a multi-miRNA prognostic expression signature. To this end, we assessed the expression of 754 miRNAs with qRT-PCR in FFPE samples from patients with or without distant relapse. We investigated miRNA expression associations with microsatellite instability [23] and compared expression of miRNA between CC and normal colon mucosa (NCM) samples
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