The landscape of selection in 551 Esophageal Adenocarcinomas defines genomic biomarkers for the clinic

Abstract

Esophageal Adenocarcinoma (EAC) is a poor prognosis cancer type with rapidly rising incidence. Our understanding of genetic events which drive EAC development is limited and there are few molecular biomarkers for prognostication or therapeutics. We have accumulated a cohort of 551 genomically characterised EACs (73% WGS and 27% WES) with clinical annotation and matched RNA-seq. Using a variety of driver detection methods we discover 65 EAC driver genes (66% novel in EAC) and describe mutation and CNV types with specific functional impact. We calculate a median of 3.7 driver events per case however exome-wide dNdS rates suggests EAC has an even higher number of driver mutations undergoing positive selection. We see mutual exclusivity or co-occurrence of events within and between a number of EAC pathways (GATA factors, Core Cell cycle genes, TP53 regulators and the SWI/SNF complex) suggestive of important functional relationships. These driver variants correlate with tumour differentiation, sex bias and prognosis. Poor prognostic indicators (SMAD4, GATA4) are verified in independent cohorts with significant predictive value. Over 50% of EACs contain sensitising events for CDK4/6 inhibitors which are highly correlated with clinically relevant sensitivity in a panel of EAC cell lines.

More information

Identifiers

ORCID for Timothy Underwood: orcid.org/0000-0001-9455-2188

Catalogue record

Export record

Altmetrics