Integrated genomic analysis of recurrence-associated small non-coding RNAs in oesophageal cancer

Gut. 2017 Feb;66(2):215-225. doi: 10.1136/gutjnl-2015-311238. Epub 2016 Aug 9.

Abstract

Objective: Oesophageal squamous cell carcinoma (ESCC) is a heterogeneous disease with variable outcomes that are challenging to predict. A better understanding of the biology of ESCC recurrence is needed to improve patient care. Our goal was to identify small non-coding RNAs (sncRNAs) that could predict the likelihood of recurrence after surgical resection and to uncover potential molecular mechanisms that dictate clinical heterogeneity.

Design: We developed a robust prediction model for recurrence based on the analysis of the expression profile data of sncRNAs from 108 fresh frozen ESCC specimens as a discovery set and assessment of the associations between sncRNAs and recurrence-free survival (RFS). We also evaluated the mechanistic and therapeutic implications of sncRNA obtained through integrated analysis from multiple datasets.

Results: We developed a risk assessment score (RAS) for recurrence with three sncRNAs (microRNA (miR)-223, miR-1269a and nc886) whose expression was significantly associated with RFS in the discovery cohort (n=108). RAS was validated in an independent cohort of 512 patients. In multivariable analysis, RAS was an independent predictor of recurrence (HR, 2.27; 95% CI, 1.26 to 4.09; p=0.007). This signature implies the expression of ΔNp63 and multiple alterations of driver genes like PIK3CA. We suggested therapeutic potentials of immune checkpoint inhibitors in low-risk patients, and Polo-like kinase inhibitors, mammalian target of rapamycin (mTOR) inhibitors, and histone deacetylase inhibitors in high-risk patients.

Conclusion: We developed an easy-to-use prognostic model with three sncRNAs as robust prognostic markers for postoperative recurrence of ESCC. We anticipate that such a stratified and systematic, tumour-specific biological approach will potentially contribute to significant improvement in ESCC treatment.

Keywords: CANCER IMMUNOBIOLOGY; GENE EXPRESSION; OESOPHAGEAL CANCER; RNA EXPRESSION; SURGICAL ONCOLOGY.

Publication types

  • Validation Study

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Carcinoma, Squamous Cell / drug therapy
  • Carcinoma, Squamous Cell / genetics*
  • Carcinoma, Squamous Cell / surgery
  • Cell Cycle Proteins / antagonists & inhibitors
  • Cell Line, Tumor / drug effects
  • Class I Phosphatidylinositol 3-Kinases
  • Disease-Free Survival
  • Drug Screening Assays, Antitumor
  • Esophageal Neoplasms / drug therapy
  • Esophageal Neoplasms / genetics*
  • Esophageal Neoplasms / surgery
  • Female
  • Genomics
  • Histone Deacetylase Inhibitors / pharmacology
  • Humans
  • Male
  • MicroRNAs / analysis*
  • MicroRNAs / genetics
  • Middle Aged
  • Models, Biological
  • Molecular Targeted Therapy
  • Neoplasm Recurrence, Local / genetics*
  • Phosphatidylinositol 3-Kinases / genetics
  • Predictive Value of Tests
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Risk Assessment
  • Systems Biology
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • Transcription Factors / genetics
  • Tumor Suppressor Proteins / genetics

Substances

  • Antineoplastic Agents
  • Cell Cycle Proteins
  • Histone Deacetylase Inhibitors
  • MIRN1269 microRNA, human
  • MIRN223 microRNA, human
  • MIRN886 microRNA, human
  • MicroRNAs
  • Proto-Oncogene Proteins
  • TP63 protein, human
  • Transcription Factors
  • Tumor Suppressor Proteins
  • TOR Serine-Threonine Kinases
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human
  • Protein-Serine-Threonine Kinases
  • polo-like kinase 1