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Nat Genet. 2019 Feb 4. doi: 10.1038/s41588-018-0331-5. [Epub ahead of print]

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

Author information

1
MRC cancer unit, Hutchison/MRC research Centre, University of Cambridge, Cambridge, UK.
2
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
3
European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Hinxton, UK.
4
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.

PMID:
30718927
DOI:
10.1038/s41588-018-0331-5

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