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

AM Frankell, View ORCID ProfileS Jammula, X Li, View ORCID ProfileG Contino, View ORCID ProfileS Killcoyne, S Abbas, View ORCID ProfileJ Perner, View ORCID ProfileL Bower, View ORCID ProfileG Devonshire, E Ococks, N Grehan, J Mok, M O’Donovan, S MacRae, M Eldridge, S Tavare, RC Fitzgerald, the Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium
doi: https://doi.org/10.1101/310029
AM Frankell
1MRC cancer unit, Hutchison/MRC research centre, University of Cambridge, Cambridge, UK
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S Jammula
2CRUK Cambridge institute, University of Cambridge, Cambridge, UK.
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X Li
1MRC cancer unit, Hutchison/MRC research centre, University of Cambridge, Cambridge, UK
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G Contino
1MRC cancer unit, Hutchison/MRC research centre, University of Cambridge, Cambridge, UK
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S Killcoyne
1MRC cancer unit, Hutchison/MRC research centre, University of Cambridge, Cambridge, UK
3European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Hinxton, UK
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S Abbas
1MRC cancer unit, Hutchison/MRC research centre, University of Cambridge, Cambridge, UK
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J Perner
2CRUK Cambridge institute, University of Cambridge, Cambridge, UK.
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L Bower
2CRUK Cambridge institute, University of Cambridge, Cambridge, UK.
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G Devonshire
2CRUK Cambridge institute, University of Cambridge, Cambridge, UK.
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E Ococks
1MRC cancer unit, Hutchison/MRC research centre, University of Cambridge, Cambridge, UK
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N Grehan
1MRC cancer unit, Hutchison/MRC research centre, University of Cambridge, Cambridge, UK
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J Mok
1MRC cancer unit, Hutchison/MRC research centre, University of Cambridge, Cambridge, UK
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M O’Donovan
4Department of Histopathology, Cambridge University Hospital NHS Trust, Cambridge, UK
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S MacRae
1MRC cancer unit, Hutchison/MRC research centre, University of Cambridge, Cambridge, UK
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M Eldridge
2CRUK Cambridge institute, University of Cambridge, Cambridge, UK.
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S Tavare
2CRUK Cambridge institute, University of Cambridge, Cambridge, UK.
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RC Fitzgerald
1MRC cancer unit, Hutchison/MRC research centre, University of Cambridge, Cambridge, UK
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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 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.

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Posted August 15, 2018.
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The landscape of selection in 551 Esophageal Adenocarcinomas defines genomic biomarkers for the clinic
AM Frankell, S Jammula, X Li, G Contino, S Killcoyne, S Abbas, J Perner, L Bower, G Devonshire, E Ococks, N Grehan, J Mok, M O’Donovan, S MacRae, M Eldridge, S Tavare, RC Fitzgerald, the Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium
bioRxiv 310029; doi: https://doi.org/10.1101/310029
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The landscape of selection in 551 Esophageal Adenocarcinomas defines genomic biomarkers for the clinic
AM Frankell, S Jammula, X Li, G Contino, S Killcoyne, S Abbas, J Perner, L Bower, G Devonshire, E Ococks, N Grehan, J Mok, M O’Donovan, S MacRae, M Eldridge, S Tavare, RC Fitzgerald, the Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium
bioRxiv 310029; doi: https://doi.org/10.1101/310029

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