Frankell, AM;
Jammula, S;
Li, X;
Contino, G;
Killcoyne, S;
Abbas, S;
Perner, J;
... Fitzgerald, RC; + view all
(2019)
The landscape of selection in 551 esophageal adenocarcinomas defines genomic biomarkers for the clinic.
Nature Genetics
, 51
pp. 506-516.
10.1038/s41588-018-0331-5.
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Lovat_The landscape of selection in 551 esophageal adenocarcinomas defines genomic biomarkers for the clinic_AAM2.pdf - Accepted Version Download (8MB) | Preview |
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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