A validated miRNA profile predicts response to therapy in esophageal adenocarcinoma

Abstract

BACKGROUNDIn the current study we present a validated miRNA signature to predict pathologic complete response (pCR) to neoadjuvant chemoradiation in esophageal adenocarcinoma.METHODSThree patient cohorts (discovery, n = 10; model, n = 43; and validation, n = 65) with locally advanced esophageal adenocarcinoma were analyzed. In the discovery cohort 754 miRNAs were examined in pretreatment tumor biopsy specimens using a TaqMan array. Of these, the 44 most significantly altered between tumors with pCR and non-pCR were examined in an additional 43 tumors using a Fluidigm 48.48 array. The 4 miRNAs (mir-505*, mir-99b, mir-451, and mir-145*) significantly predicting pCR in both cohorts were examined in an additional validation cohort (n = 65) using an Illumina array. These 4 miRNAs were used to generate an miRNA expression profile (MEP) score.RESULTSThe 4 miRNAs profiled are highly significantly associated with pCR in the model cohort (Ptrend =.008), the validation cohort (Ptrend =.025), and the combined cohort (Ptrend = 4.6 × 10−4). The receiver-operator characteristic areas under the curves (AUCs) for the MEP score were 0.78 for the model cohort, 0.71 for the validation cohort, and 0.72 for the combined cohort. When combined with clinical variables, the MEP score AUCs increased to 0.89, 0.77, and 0.81, respectively Estimates from logistic regression based on the MEP were determined and used to generate a probability of pCR plot, which identifies a group of patients with very high (≥80%) and very low (≤10%) probability of pCR.CONCLUSIONSThe MEP score provides a validated means of predicting pCR to neoadjuvant chemoradiotherapy in esophageal adenocarcinoma that is robust across several analysis platforms. Cancer 2014;120:3635–3641.

Low MiR-187 Expression Promotes Resistance to Chemoradiation Therapy In Vitro and Correlates with Treatment Failure in Patients with Esophageal Adenocarcinoma

“…Mounting evidence suggests that miRNA profiles may be more efficient than gene profiles in discriminating different disease states and diseased versus nondiseased states (9,10). A role for miRNAs has been implicated in the pathogenesis of EAC, with several potential diagnostic and prognostic miRNA markers identified (11,12). We have previously demonstrated that both miR-31 (13) and miR-330-5p (14) are significantly decreased in pretreatment tumor biopsies from esophageal cancer patients who subsequently have a poor response to neoadjuvant CRT, highlighting a potential role for these miRNAs in the tumor response to CRT.…”

“…These data support miR-187-mediated regulation of these gene targets in EAC cells. Given the decreased expression of miR-187 in EAC tumors from poor responders, this suggests that the genes and/or pathways downregulated by miR-187 are likely to demonstrated that dysregulation of four miRNAs (miR-505*, miR-99b, miR-451 and miR-145*) was significantly associated with a pCR (12). Three miRNAs (miR-145*, miR-886-5p and miR-720) that we identified as being altered between responders and nonresponders in this study were also highlighted by Skinner and colleagues in pCR versus non-pCR patients.…”

Nomogram for predicting pathologically complete response after neoadjuvant chemoradiotherapy for oesophageal cancer

“…In this context recent studies have shown promising markers such as stem cell markers in oesophageal cancer [44] and microRNAs as predictive biomarkers for response [45]. These findings have not yet been validated and their clinical relevance needs to be further elucidated.…”

The combined use of miRNAs and mRNAs as biomarkers for the diagnosis of papillary thyroid carcinoma

“…miRNAs regulate gene expression at the post-transcriptional level by binding to the 3'-UTR of their target mRNAs (13). A number of studies have demonstrated that miRNA expression is associated with cell proliferation, metastasis, invasion and and response to therapy (14)(15)(16)(17)(18)(19)(20). miRNA expression differs between cancer tissues and adjacent normal tissues in patients (21)(22)(23).…”