Overexpression of miR-21-5p as a predictive marker for complete tumor regression to neoadjuvant chemoradiotherapy in rectal cancer patients

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Lopes-Ramos, Camila Miranda ^{[1, 2]} ; Habr-Gama, Angelita ^{[3, 4]} ; Quevedo, Bruna de Souza ^[5] ; Felcio, Natlia Mariana ^{[3, 6]} ; Bettoni, Fabiana ^[1] ; Koyama, Fernanda Christtanini ^[1] ; Asprino, Paula Fontes ^[1] ; Galante, Pedro Alexandre ^[1] ; Gama-Rodrigues, Joaquim ^{[3, 4]} ; Camargo, Anamaria Aranha ^{[1, 5]} ; Perez, Rodrigo Oliva ^{[3, 4, 5]} ; Parmigiani, Raphael Bessa ^[1]

Afiliação do(s) autor(es)

^[1] Hosp Srio Libans, Ctr Oncol Mol, So Paulo - Brazil

^[2] Fundao Antnio Prudente, So Paulo - Brazil

^[3] Angelita & Joaquim Gama Inst, So Paulo - Brazil

^[4] Univ Sao Paulo, Sch Med, So Paulo - Brazil

^[5] Ludwig Inst Canc Res, So Paulo - Brazil

^[6] Hosp Alemo Oswaldo Cruz, So Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: BMC MEDICAL GENOMICS; v. 7, DEC 11 2014.
• Citações Web of Science: 34

Resumo

Background: Neoadjuvant chemoradiotherapy (nCRT) followed by radical surgery is the preferred treatment strategy for locally advanced rectal cancer. However, complete tumor regression is observed in a significant proportion of patients after nCRT, making them ideal candidates for alternative treatment strategies to this considerably morbid procedure. Identification of such patients based on clinical findings (complete clinical response - cCR) is difficult mainly because it relies on subjective clinical and imaging studies. Our goal was to identify biomarkers capable of predicting complete response to nCRT. Methods: We analyzed miRNA expression profile using deep sequencing in rectal tumor biopsies prior to nCRT. Differential expression was investigated by EdgeR for a training (n = 27) and a validation (n = 16) set of patients to identify miRNAs associated with treatment response (complete vs. incomplete). In vitro experiments with two cancer cell lines were also performed in order to evaluate the possible role of miRNAs on response to nCRT. Results: We found 4 miRNAs differentially expressed between complete and incomplete responders to nCRT. In addition, validation was performed using an independent group of patients and miR-21-5p was confirmed as being overexpressed in complete responders. Overall sensitivity and specificity of miR-21-5p expression in predicting complete response to nCRT was 78% and 86% respectively. Interestingly, in a subset of patients with cCR followed by early local recurrence, the expression level of miR-21-5p was considerably low, similarly to incomplete responders. We also found SATB1, a miR-21-5p target gene and known multidrug resistance gene, whose expression was inversely correlated with miR-21-5p expression. Finally, we performed functional experiments and showed that miR-21-5p and SATB1 may be directly involved with poor response to nCRT in rectal cancer patients. Conclusions: This study suggests miR-21-5p as a promising predictive biomarker, which should aid in the selection of patients with cCR to nCRT that potentially could be spared from radical surgery. (AU)

• Processo FAPESP: 09/17785-5 - Identificação e estudo de expressão de variantes de poliadenilação e de microRNAs através de sequenciamento em larga escala em amostras de tumor colorretal
• Beneficiário: Camila Miranda Lopes Ramos
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 09/54349-9 - Identificacao e estudo de expressao de variantes de poliadenilacao e de micrornas atraves de sequenciamento em larga escala.
• Beneficiário: Raphael Bessa Parmigiani
• Modalidade de apoio: Auxílio à Pesquisa - Regular