Syddansk Universitet Association between the expression of microRNAs and the response of patients with locally advanced rectal cancer to preoperative chemoradiotherapy

Preoperative chemoradiotherapy (CRT) followed by mesorectal excision is the standard treatment for patients with locally advanced rectal cancer (LARC). The balance between treatment efficacy and toxicity is a major issue in the clinical management of these patients. There is a requirement for the identification of predictive molecular biomarkers for the response of patients to CRT. The present study aimed to analyze the association between microRNA (miRNA/miR) expression and treatment efficacy in patients with LARC who were treated with preoperative CRT. From previous clinical trials, 55 patients for the test cohort and 130 patients for the validation cohort met the criteria for the present investigation. Through reverse transcription‐quantitative polymerase chain reaction analysis, the expression of miR-21, -31, -125b, -145 and -630 in the diagnostic biopsies was analyzed. The primary endpoint of tumor regression was evaluated according to Mandard's Tumor Regression Grade (TRG) system. In the test cohort, a significant association was identified between low miRNA-145 expression and TRG1+2 (P=0.0003). Similarly, this association was identified in the validation cohort, although it did not reach statistical significance. Furthermore, a significant association between high miRNA‐21 expression and TRG1+2 (P=0.035) was observed in the validation cohort. The remaining miRNAs analyzed were not associated with TRG. The results of the present study highlight the clinical importance of miRNAs in LARC and underline the necessity for validation studies in this setting. Introduction Preoperative 5‐fluorouracil‐based chemoradiotherapy (CRT) followed by mesorectal excision is the standard treatment for patients with locally advanced rectal cancer (LARC) (1-3). Several previous studies have demonstrated that CRT significantly downstages the disease and reduces the risk of local tumor recurrence (4-6). The response rate to CRT in this group varies, with 9-30% of patients having a pathological complete response (pCR) and 46‐60% achieving some degree of tumor downstaging (7,8). An improved long‐term outcome has been demonstrated for patients with pCR compared with patients who are non-responsive to CRT (9-12); however, this treatment has several long-term side effects. Therefore, the appropriate selection of patients who will respond to CRT is important. At present, only certain clinical parameters and radiological investigations are available for use in the selection of patients for CRT, which is insufficient. There is a requirement for biomarkers that are able to predict the effect of preoperative CRT. MicroRNAs (miRNAs/miRs) are short (18‐25 nucleotides) non‐coding RNA molecules that act as negative gene regulators at the post‐transcriptional level. miRNAs serve an important role in the regulation of biological processes, such as cell differentiation, proliferation and apoptosis. Numerous miRNAs interfere with the expression of oncogenes and tumor suppressor genes with a direct involvement in carcinogenesis (13,14). Due to their association with cancer, miRNAs are being investigated as potential diagnostic and prognostic biomarkers, and predictors of treatment response (15,16). In the present study, 5 miRNAs were chosen for study based on the literature and our group's previous methodological work. In rectal cancer tissue, reference genes (miR‐193a‐5p, miR ‐27a and let‐7g) for the relative quantification of miRNAs have previously been identified (17) and the intratumoral heterogeneity of the present panel of miRNAs (miR-21, -31, -125b, -145 and -630) has been assessed (18). miRNA-21 is overexpressed in rectal cancer and its downregulation following neoadjuvant CRT has been Association between the expression of microRNAs and the response of patients with locally advanced rectal cancer to preoperative chemoradiotherapy ANNE HAAHR MELLERGAARD ERIKSEN1,2, FLEMMING BRANDT SØRENSEN2,3, RIKKE FREDSLUND ANDERSEN4, ANDERS JAKOBSEN1,2 and TORBEN FRØSTRUP HANSEN1,2 1Department of Oncology, Danish Colorectal Cancer Center South, Vejle Hospital, 7100 Vejle; 2Institute of Regional Health Research, University of Southern Denmark, 5000 Odense; Departments of 3Clinical Pathology and 4Clinical Biochemistry, Danish Colorectal Cancer Center South, Vejle Hospital, 7100 Vejle, Denmark Received September 27, 2016; Accepted January 6, 2017 DOI: 10.3892/ol.2017. 6141 Correspondence to: Dr Anne Haahr Mellergaard Eriksen, Department of Oncology, Danish Colorectal Cancer Center South, Vejle Hospital, Kabbeltoft 25, 7100 Vejle, Denmark E‐mail: anne.haahr. mellergaard@rsyd.dk