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

Esophageal adenocarcinoma (EAC) is a poor prognosis cancer type with rapidly rising incidence. Our understanding of genetic events that drive 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-seq, we discover 77 EAC driver genes and 21 non-coding driver elements. We identify a mean of 4.4 driver events per tumor, derived more commonly from mutations rather than copy number alterations, and compare these mutations to the exome-wide mutational excess using dN/dS calculations. We observe mutual exclusivity or co-occurrence of events within and between a number of dysregulated EAC pathways, suggestive of strong functional relationships. Poor prognostic indicators (SMAD4, GATA4) are verified in independent cohorts with significant predictive value. Over 50% of EACs contain sensitizing events for CDK4/6 inhibitors, which are highly correlated with clinically relevant sensitivity in a panel EAC cell lines and organoids.