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

Authors
  • Frankell, AM
  • Jammula, S
  • Li, X
  • Contino, G
  • Killcoyne, S
  • Abbas, S
  • Perner, J
  • Bower, L
  • Devonshire, G
  • Cocks, E
  • Grehan, N
  • Mok, J
  • O'Donovan, M
  • MacRae, S
  • Eldridge, MD
  • Tavare, S
  • Fitzgerald, RC
  • Noorani, A
  • Edwards, PAW
  • Grehanl, N
  • And 73 more
Publication Date
Dec 10, 2018
Source
Spiral - Imperial College Digital Repository
Keywords
License
Unknown
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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.

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