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Identification of microRNA Biomarkers of Response to Neoadjuvant Chemoradiotherapy in Esophageal Adenocarcinoma Using Next Generation Sequencing

  • Gastrointestinal Oncology
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

Clinical trials report improved overall survival following neoadjuvant chemoradiotherapy in patients undergoing surgery for esophageal adenocarcinoma, with a 10–15% survival improvement. MicroRNAs (miRNAs) are small noncoding RNAs that are known to direct the behavior of cancers, including response to treatment. We investigated the ability of miRNAs to predict outcomes after neoadjuvant chemoradiotherapy.

Methods

Endoscopic biopsies from esophageal adenocarcinomas were obtained before neoadjuvant chemoradiotherapy and esophagectomy. miRNA levels were measured in the biopsies using next generation sequencing and compared with pathological response in the surgical resection, and subsequent survival. miRNA ratios that predicted pathological response were identified by Lasso regression and leave-one-out cross-validation. Association between miRNA ratio candidates and relapse-free survival was assessed using Kaplan–Meier analysis. Cox regression and Harrell’s C analyses were performed to assess the predictive performance of the miRNAs.

Results

Two miRNA ratios (miR-4521/miR-340-5p and miR-101-3p/miR-451a) that predicted the pathological response to neoadjuvant chemoradiotherapy were found to be associated with relapse-free survival. Pretreatment expression of these two miRNA ratios, pretreatment tumor differentiation, posttreatment AJCC histopathological tumor regression grading, and posttreatment tumor clearance/margins were significant factors associated with survival in Cox regression analysis. Multivariate analysis of the two ratios together with pretherapy factors resulted in a risk prediction accuracy of 85% (Harrell’s C), which was comparable with the prediction accuracy of the AJCC treatment response grading (77%).

Conclusions

miRNA-ratio biomarkers identified using next generation sequencing can be used to predict disease free survival following neoadjuvant chemoradiotherapy and esophagectomy in patients with esophageal adenocarcinoma.

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Acknowledgment

The authors thank Peter Devitt for assistance with sample identification, and members of the ACRF Cancer Genomics Facility including Joel Geoghegan, David Lawrence, Andreas Schreiber, and Anna Tsykin. Funding for this study was from NHMRC Project Grant APP595964, and a project grant awarded by Tour de Cure Australia.

Author information

Author notes

  1. Karen Chiam and George C. Mayne have contributed equally to this work.

Authors and Affiliations

  1. Cancer Research Division, Cancer Council New South Wales, Sydney, Australia

    Karen Chiam PhD

  2. Discipline of Surgery, College of Medicine and Public Health, Flinders University of South Australia, Adelaide, SA, Australia

    Karen Chiam PhD, George C. Mayne BSc(Hons), PhD, David I. Watson MBBS, MD, PhD, FRACS, FRCSEd(Hon), FAHMS, Tim F. Bright MBBS, MS, FRACS, Tanya Irvine BSc(Hons), Richard Hummel MD, Tingting Wang BSc(Hons) & Damian J. Hussey BSc(Hons), PhD

  3. Flinders Centre for Innovation in Cancer, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia

    George C. Mayne BSc(Hons), PhD, David I. Watson MBBS, MD, PhD, FRACS, FRCSEd(Hon), FAHMS, Tim F. Bright MBBS, MS, FRACS, Michael Z. Michael BSc(Hons), PhD, Christos S. Karapetis MBBS, MMedSc, Tanya Irvine BSc(Hons), Tingting Wang BSc(Hons), Letitia K. Pimlott BSc(Hons), Shashikanth Marri PhD & Damian J. Hussey BSc(Hons), PhD

  4. Flinders Centre for Epidemiology and Biostatistics, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia

    Richard J. Woodman PhD

  5. Cancer Biology and Surgical Oncology Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia

    Wayne A. Phillips BSc(Hons), PhD

  6. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia

    Wayne A. Phillips BSc(Hons), PhD

  7. Department of Surgery, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany

    Richard Hummel MD

  8. Department of Anatomical Pathology, Flinders Medical Centre, Adelaide, SA, Australia

    David StJ. Astill A/Dip Med Lab Sci, BSc Hons, BMBS, PhD, FRCPA

  9. Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia

    Andrew R. Ruszkiewicz MD, FRCPA

  10. Department of Surgery, University of Adelaide, Royal Adelaide Hospital, Adelaide, SA, Australia

    Sarah K. Thompson MD, PhD, FRACS

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  1. Karen Chiam PhD
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Correspondence to Damian J. Hussey BSc(Hons), PhD.

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Chiam, K., Mayne, G.C., Watson, D.I. et al. Identification of microRNA Biomarkers of Response to Neoadjuvant Chemoradiotherapy in Esophageal Adenocarcinoma Using Next Generation Sequencing. Ann Surg Oncol 25, 2731–2738 (2018). https://doi.org/10.1245/s10434-018-6626-z

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