UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

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

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. Green open access

[img]
Preview
Text
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.

Type: Article
Title: The landscape of selection in 551 esophageal adenocarcinomas defines genomic biomarkers for the clinic
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/s41588-018-0331-5
Publisher version: https://doi.org/10.1038/s41588-018-0331-5
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Bioinformatics, Gastrointestinal cancer, Genomics, Oesophageal diseases, Translational research
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Genetics, Evolution and Environment
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Surgery and Interventional Sci
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Surgery and Interventional Sci > Department of Targeted Intervention
URI: https://discovery.ucl.ac.uk/id/eprint/10069342
Downloads since deposit
39Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item