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Annals of Surgical Oncology

, Volume 25, Issue 9, pp 2731–2738 | Cite as

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

  • Karen Chiam
  • George C. Mayne
  • David I. Watson
  • Richard J. Woodman
  • Tim F. Bright
  • Michael Z. Michael
  • Christos S. Karapetis
  • Tanya Irvine
  • Wayne A. Phillips
  • Richard Hummel
  • Tingting Wang
  • Letitia K. Pimlott
  • Shashikanth Marri
  • David StJ. Astill
  • Andrew R. Ruszkiewicz
  • Sarah K. Thompson
  • Damian J. Hussey
Gastrointestinal Oncology

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.

Notes

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.

Supplementary material

10434_2018_6626_MOESM1_ESM.docx (2 mb)
Supplementary material 1 (DOCX 2050 kb)

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Copyright information

© Society of Surgical Oncology 2018

Authors and Affiliations

  • Karen Chiam
    • 1
    • 2
  • George C. Mayne
    • 2
    • 3
  • David I. Watson
    • 2
    • 3
  • Richard J. Woodman
    • 4
  • Tim F. Bright
    • 2
    • 3
  • Michael Z. Michael
    • 3
  • Christos S. Karapetis
    • 3
  • Tanya Irvine
    • 2
    • 3
  • Wayne A. Phillips
    • 5
    • 6
  • Richard Hummel
    • 2
    • 7
  • Tingting Wang
    • 2
    • 3
  • Letitia K. Pimlott
    • 3
  • Shashikanth Marri
    • 3
  • David StJ. Astill
    • 8
  • Andrew R. Ruszkiewicz
    • 9
  • Sarah K. Thompson
    • 10
  • Damian J. Hussey
    • 2
    • 3
  1. 1.Cancer Research DivisionCancer Council New South WalesSydneyAustralia
  2. 2.Discipline of Surgery, College of Medicine and Public HealthFlinders University of South AustraliaAdelaideAustralia
  3. 3.Flinders Centre for Innovation in Cancer, College of Medicine and Public HealthFlinders UniversityAdelaideAustralia
  4. 4.Flinders Centre for Epidemiology and Biostatistics, College of Medicine and Public HealthFlinders UniversityAdelaideAustralia
  5. 5.Cancer Biology and Surgical Oncology LaboratoryPeter MacCallum Cancer CentreMelbourneAustralia
  6. 6.Sir Peter MacCallum Department of OncologyUniversity of MelbourneParkvilleAustralia
  7. 7.Department of SurgeryUniversity Hospital Schleswig-Holstein, Campus LübeckLübeckGermany
  8. 8.Department of Anatomical PathologyFlinders Medical CentreAdelaideAustralia
  9. 9.Centre for Cancer BiologyUniversity of South Australia and SA PathologyAdelaideAustralia
  10. 10.Department of SurgeryUniversity of Adelaide, Royal Adelaide HospitalAdelaideAustralia

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