PT  - JOURNAL ARTICLE
AU  - AM Frankell
AU  - S Jammula
AU  - X Li
AU  - G Contino
AU  - S Killcoyne
AU  - S Abbas
AU  - J Perner
AU  - L Bower
AU  - G Devonshire
AU  - E Ococks
AU  - N Grehan
AU  - J Mok
AU  - M O’Donovan
AU  - S MacRae
AU  - M Eldridge
AU  - S Tavare
AU  - RC Fitzgerald
AU  - the Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium
TI  - The landscape of selection in 551 Esophageal Adenocarcinomas defines genomic biomarkers for the clinic
AID  - 10.1101/310029
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 310029
4099  - http://biorxiv.org/content/early/2018/08/15/310029.short
4100  - http://biorxiv.org/content/early/2018/08/15/310029.full
AB  - 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 gene detection methods, we discover 77 EAC driver genes (73% novel) and 21 non-coding driver elements (95% novel), and describe mutation and CNV types with specific functional impact. We identify a mean of 4.4 driver events per case derived from both copy number events and mutations. We compare driver mutation rates to the exome-wide mutational excess calculated using Non-synonymous vs Synonymous mutation rates (dNdS). We observe 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 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 EAC cell lines and organoids.