TY - JOUR
T1 - The landscape of selection in 551 esophageal adenocarcinomas defines genomic biomarkers for the clinic
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 - Scott, Michael
AU - Turkington, Richard
AU - McManus, Damian
AU - Coleman, Helen
AU - The Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium
PY - 2019/3/1
Y1 - 2019/3/1
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.
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 -