The landscape of selection in 551 esophageal adenocarcinomas defines genomic biomarkers for the clinic

Research output: Contribution to journalArticlepeer-review

Authors

  • Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium
  • Gianmarco Contino

Colleges, School and Institutes

External organisations

  • University of Cambridge
  • Cancer Research UK Cambridge Institute
  • European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom, CB10 1SD.
  • MRC cancer unit, Hutchison/MRC research Centre, University of Cambridge, Cambridge, UK. rcf29@mrc-cu.cam.ac.uk.

Abstract

Esophageal adenocarcinoma (EAC) is a poor-prognosis cancer type with rapidly rising incidence. Understanding of the genetic events driving EAC development is limited, and there are few molecular biomarkers for prognostication or therapeutics. Using a cohort of 551 genomically characterized EACs with matched RNA sequencing data, we discovered 77 EAC driver genes and 21 noncoding driver elements. We identified a mean of 4.4 driver events per tumor, which were derived more commonly from mutations than copy number alterations, and compared the prevelence of these mutations to the exome-wide mutational excess calculated using non-synonymous to synonymous mutation ratios (dN/dS). We observed mutual exclusivity or co-occurrence of events within and between several dysregulated EAC pathways, a result suggestive of strong functional relationships. Indicators of poor prognosis (SMAD4 and GATA4) were verified in independent cohorts with significant predictive value. Over 50% of EACs contained sensitizing events for CDK4 and CDK6 inhibitors, which were highly correlated with clinically relevant sensitivity in a panel of EAC cell lines and organoids.

Details

Original languageEnglish
Pages (from-to)506-516
Number of pages16
JournalNature Genetics
Volume51
Issue number3
Early online date4 Feb 2019
Publication statusPublished - Mar 2019

Keywords

  • Adenocarcinoma/genetics, Biomarkers, Tumor/genetics, Cohort Studies, DNA Copy Number Variations/genetics, Esophageal Neoplasms/genetics, Exome/genetics, Female, Gene Expression Profiling/methods, Gene Expression Regulation, Neoplastic/genetics, Genomics/methods, Humans, Male, Mutation/genetics