Journal
NATURE GENETICS
Volume 51, Issue 3, Pages 506-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41588-018-0331-5
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Funding
- Cancer Research UK [RG66287]
- Medical Research Council
- UK National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre, from Addenbrooke's Hospital
- MRC [MC_UU_12022/2, MR/M009157/1] Funding Source: UKRI
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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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