The landscape of selection in 551 esophageal adenocarcinomas defines genomic biomarkers for the clinic
File(s)
Accepted version
Author(s)
Type
Journal Article
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.
Date Issued
2019-03-01
Date Acceptance
2018-12-10
Citation
Nature Genetics, 2019, 51 (3), pp.506-516
ISSN
1061-4036
Publisher
Nature Research
Start Page
506
End Page
516
Journal / Book Title
Nature Genetics
Volume
51
Issue
3
Copyright Statement
© 2019 Springer-Verlag. The final publication is available at Springer via https://doi.org/10.1038/s41588-018-0331-5
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000459947200018&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Subjects
Science & Technology
Life Sciences & Biomedicine
Genetics & Heredity
COMPREHENSIVE MOLECULAR CHARACTERIZATION
ACQUIRED-RESISTANCE
SOMATIC MUTATIONS
PD-1 BLOCKADE
CANCER
SIGNATURES
CARCINOMA
PATHWAYS
PATTERNS
DRIVER
Publication Status
Published
Date Publish Online
2019-02-04