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

Frankell AM1, Jammula S2, Li X1, Contino G1, Killcoyne S1,3, Abbas S1, Perner J2, Bower L2, Devonshire G2, Ococks E1, Grehan N1, Mok J1, O'Donovan M, MacRae S1, Eldridge MD2, Tavaré S2; Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium, Fitzgerald RC4.

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.