The Clinical Significance of MiR-148a as a Predictive Biomarker in Patients with Advanced Colorectal Cancer

Masanobu Takahashi,Yuji Toiyama,Keun Hur,Ajay Goel,C Richard Boland,Antoni Castells,Francesc Balaguer,Miriam Cuatrecasas,Alfons Navarro

doi:10.1371/journal.pone.0046684

Abstract

AimDevelopment of robust prognostic and/or predictive biomarkers in patients with colorectal cancer (CRC) is imperative for advancing treatment strategies for this disease. We aimed to determine whether expression status of certain miRNAs might have prognostic/predictive value in CRC patients treated with conventional cytotoxic chemotherapies.MethodsWe studied a cohort of 273 CRC specimens from stage II/III patients treated with 5-fluorouracil-based adjuvant chemotherapy and stage IV patients subjected to 5-fluorouracil and oxaliplatin-based chemotherapy. In a screening set (n = 44), 13 of 21 candidate miRNAs were successfully quantified by multiplex quantitative RT-PCR. In the validation set comprising of the entire patient cohort, miR-148a expression status was assessed by quantitative RT-PCR, and its promoter methylation was quantified by bisulfite pyrosequencing. Lastly, we analyzed the associations between miR-148a expression and patient survival.ResultsAmong the candidate miRNAs studied, miR-148a expression was most significantly down-regulated in advanced CRC tissues. In stage III and IV CRC, low miR-148a expression was associated with significantly shorter disease free-survival (DFS), a worse therapeutic response, and poor overall survival (OS). Furthermore, miR-148a methylation status correlated inversely with its expression, and was associated with worse survival in stage IV CRC. In multivariate analysis, miR-148a expression was an independent prognostic/predictive biomarker for advanced CRC patients (DFS in stage III, low vs. high expression, HR 2.11; OS in stage IV, HR 1.93).DiscussionMiR-148a status has a prognostic/predictive value in advanced CRC patients treated with conventional chemotherapy, which has important clinical implications in improving therapeutic strategies and personalized management of this malignancy.

Highlights

Colorectal cancer (CRC) patients with lymph node metastasis (TNM stage III) are treated with adjuvant chemotherapy that includes cytotoxic drugs such as 5-fluorouracil (5-FU) and oxaliplatin, following surgical resection of the cancer
Only miR-148a revealed a significant down-regulation in tumors with lymph node or distant metastasis (IV) compared to tumors without (II), which underscores the significance of this miRNA in colorectal cancer (CRC) progression/ metastasis
CRCs with low miR-148a expression ascertained by quantified by Taqman reverse transcription-PCR (qRT-PCR) revealed very low or absent expression of this miRNA at the In situ hybridization (ISH) level (Figure 1B). These results indicate that our qRT-PCR results accurately reflected the endogenous expression of miR-148a within the cancer cells obtained from CRC tissue specimens

Summary

Introduction

Colorectal cancer (CRC) patients with lymph node metastasis (TNM stage III) are treated with adjuvant chemotherapy that includes cytotoxic drugs such as 5-fluorouracil (5-FU) and oxaliplatin, following surgical resection of the cancer. Patients with distant metastatic CRC (stage IV) are treated with various combinations of chemotherapeutic drugs and molecularlytargeted drugs that include anti-VEGF and anti-EGFR antibodies. These treatment regimens have improved outcomes in patients with advanced CRC, a significant proportion of individuals fail to derive any benefit from such treatments, and some experience worse outcomes as a result of drug-associated toxicities. Microsatellite instability (MSI), a phenotype present in ,15% of CRCs, has been shown to associate with improved overall survival (OS) regardless of adjuvant chemotherapy, as well as a lack of benefit from 5-FU-

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