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, University of Cambridge, Li Ka Shing Centre, Cambridge Department of Oncology, University of Cambridge, Addenbrooke's Hospital, Cambridge Cambridge Experimental Cancer Medicine Centre and NIHR Cambridge Biomedical Research Centre, Cambridge, UK.
  • 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
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