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Tumor microRNAs Identified by Small RNA Sequencing as Potential Response Predictors in Locally Advanced Rectal Cancer Patients Treated With Neoadjuvant Chemoradiotherapy

T. Machackova, K. Trachtova, V. Prochazka, T. Grolich, M. Farkasova, L. Fiala, R. Sefr, I. Kiss, M. Skrovina, M. Dosoudil, I. Berindan-Neagoe, M. Svoboda, O. Slaby, Z. Kala,

. 2020 ; 17 (3) : 249-257. [pub] -

Jazyk angličtina Země Řecko

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/bmc20028198

Grantová podpora
NV16-31765A MZ0 CEP - Centrální evidence projektů

BACKGROUND/AIM: Rectal cancer accounts for approximately one-third of all colorectal cancers. Currently, the standard treatment for locally advanced rectal cancer (LARC) is neoadjuvant chemoradiotherapy (CRT) with capecitabine or 5-fluorouracil followed by curative surgery. Unfortunately, only 20% of patients with LARC present complete pathological response after CRT, whereas in 20-40% cases the response is poor or absent. The aim of our study was to evaluate whether microRNAs (miRNAs) in tumor biopsy specimen have the potential to predict therapeutic response in LARC patients. PATIENTS AND METHODS: In total 87 LARC patients treated by CRT were enrolled in our prospective study. To identify predictive miRNAs, we used small RNA sequencing in 40 tumor biopsy samples of LARC patients (20 responders, 20 non-responders) and qPCR validation of selected miRNA candidates. RESULTS: In the discovery phase of the study, we identified 69 miRNAs to have significantly different expression between the group of responders (TRG 1,2) and a group of non-responders (TRG 4,5) to neoadjuvant CRT. Among these miRNAs, 48 showed a lower expression and 21 showed higher expression in tumor tissues from poorly responding LARC patients. Five miRNAs were selected for validation, but only miR-487a-3p was confirmed to have a significantly higher expression in the tumor biopsy specimens of non-responders to neoadjuvant CRT (p<0.0006, AUC=0.766). Gene Ontology (GO) clustering and pathway enrichment analysis of the miR-487a-3p mRNA targets, revealed potential mechanisms behind miR-487a-3p roles in chemoradioresistance (e.g. TGF-beta signaling pathway, protein kinase activity, double-stranded DNA binding, or microRNAs in cancer). CONCLUSION: By combination of miRNA expression profiling and integrative computational biology we identified miR-487a-3p as a potential predictive biomarker of CRT response in LARC patients.

Citace poskytuje Crossref.org

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$a BACKGROUND/AIM: Rectal cancer accounts for approximately one-third of all colorectal cancers. Currently, the standard treatment for locally advanced rectal cancer (LARC) is neoadjuvant chemoradiotherapy (CRT) with capecitabine or 5-fluorouracil followed by curative surgery. Unfortunately, only 20% of patients with LARC present complete pathological response after CRT, whereas in 20-40% cases the response is poor or absent. The aim of our study was to evaluate whether microRNAs (miRNAs) in tumor biopsy specimen have the potential to predict therapeutic response in LARC patients. PATIENTS AND METHODS: In total 87 LARC patients treated by CRT were enrolled in our prospective study. To identify predictive miRNAs, we used small RNA sequencing in 40 tumor biopsy samples of LARC patients (20 responders, 20 non-responders) and qPCR validation of selected miRNA candidates. RESULTS: In the discovery phase of the study, we identified 69 miRNAs to have significantly different expression between the group of responders (TRG 1,2) and a group of non-responders (TRG 4,5) to neoadjuvant CRT. Among these miRNAs, 48 showed a lower expression and 21 showed higher expression in tumor tissues from poorly responding LARC patients. Five miRNAs were selected for validation, but only miR-487a-3p was confirmed to have a significantly higher expression in the tumor biopsy specimens of non-responders to neoadjuvant CRT (p<0.0006, AUC=0.766). Gene Ontology (GO) clustering and pathway enrichment analysis of the miR-487a-3p mRNA targets, revealed potential mechanisms behind miR-487a-3p roles in chemoradioresistance (e.g. TGF-beta signaling pathway, protein kinase activity, double-stranded DNA binding, or microRNAs in cancer). CONCLUSION: By combination of miRNA expression profiling and integrative computational biology we identified miR-487a-3p as a potential predictive biomarker of CRT response in LARC patients.
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$a Trachtova, Karolina $u Central European Institute of Technology, Masaryk University, Brno, Czech Republic.
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$a Prochazka, Vladimir $u Department of Surgery, Faculty Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic.
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$a Grolich, Tomas $u Department of Surgery, Faculty Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic.
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$a Farkasova, Martina $u Department of Surgery, Faculty Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic.
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$a Skrovina, Matej $u Department of Surgery, Hospital & Oncological Centre Novy Jicin, Novy Jicin, Czech Republic. Department of Surgery I, Faculty of Medicine and Dentistry, Palacky University Olomouc and University Hospital Olomouc, Olomouc, Czech Republic.
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$a Dosoudil, Michal $u Department of Surgery, Hospital & Oncological Centre Novy Jicin, Novy Jicin, Czech Republic.
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$a Slaby, Ondrej $u Central European Institute of Technology, Masaryk University, Brno, Czech Republic Kala.Zdenek@fnbrno.cz on.slaby@gmail.com. Department of Pathology, Faculty Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic.
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