TY - JOUR
T1 - The landscape of selection in 551 esophageal adenocarcinomas defines genomic biomarkers for the clinic
AU - Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium
AU - Frankell, Alexander M.
AU - Jammula, Sri Ganesh
AU - Li, Xiaodun
AU - Contino, Gianmarco
AU - Killcoyne, Sarah
AU - Abbas, Sujath
AU - Perner, Juliane
AU - Bower, Lawrence
AU - Devonshire, Ginny
AU - Ococks, Emma
AU - Grehan, Nicola
AU - Mok, James
AU - O’Donovan, Maria
AU - MacRae, Shona
AU - Eldridge, Matthew D.
AU - Tavaré, Simon
AU - Fitzgerald, Rebecca C.
AU - Noorani, Ayesha
AU - Edwards, Paul A.W.
AU - Grehan, Nicola
AU - Nutzinger, Barbara
AU - Hughes, Caitriona
AU - Fidziukiewicz, Elwira
AU - MacRae, Shona
AU - Northrop, Alex
AU - Contino, Gianmarco
AU - Li, Xiaodun
AU - de la Rue, Rachel
AU - Katz-Summercorn, Annalise
AU - Abbas, Sujath
AU - Loureda, Daniel
AU - O’Donovan, Maria
AU - Miremadi, Ahmad
AU - Malhotra, Shalini
AU - Tripathi, Monika
AU - Tavaré, Simon
AU - Lynch, Andy G.
AU - Eldridge, Matthew
AU - Secrier, Maria
AU - Devonshire, Ginny
AU - Perner, Juliane
AU - Jammula, Sri Ganesh
AU - Davies, Jim
AU - Crichton, Charles
AU - Carroll, Nick
AU - Safranek, Peter
AU - Hindmarsh, Andrew
AU - Sujendran, Vijayendran
AU - Ang, Yeng
AU - Sharrocks, Andrew
N1 - Funding Information:
We thank A. J. Bass and N. Waddell for providing data in Dulak et al.19 and Nones et al.20, respectively, which were also included in our previous publication18. Inclusion of these data allowed for augmentation of our ICGC cohort and greater sensitivity for the detection of EAC driver variants. OCCAMS was funded by a Programme Grant from Cancer Research UK (RG66287), and the laboratory of R.C.F. is funded by a Core Programme Grant from the Medical Research Council. We thank the Human Research Tissue Bank, which is supported by the UK National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre, from Addenbrooke’s Hospital. Additional infrastructure support was provided from the Cancer Research UK–funded Experimental Cancer Medicine Centre.
Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2019/2/4
Y1 - 2019/2/4
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85061351097&partnerID=8YFLogxK
U2 - 10.1038/s41588-018-0331-5
DO - 10.1038/s41588-018-0331-5
M3 - Article
C2 - 30718927
AN - SCOPUS:85061351097
SN - 1061-4036
VL - 51
SP - 506
EP - 516
JO - Nature Genetics
JF - Nature Genetics
IS - 3
ER -