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

the Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium; Alexander M. Frankell; Sri Ganesh Jammula; Xiaodun Li; Gianmarco Contino; Sarah Killcoyne; Sujath Abbas; Juliane Perner; Lawrence Bower; Ginny Devonshire; Emma Ococks; Nicola Grehan; James Mok; Maria O’Donovan; Shona MacRae; Matthew D. Eldridge; Simon Tavaré; Rebecca C. Fitzgerald; Ayesha Noorani; Paul A.W. Edwards; Nicola Grehan; Barbara Nutzinger; Caitriona Hughes; Elwira Fidziukiewicz; Shona MacRae; Alex Northrop; Gianmarco Contino; Xiaodun Li; Rachel de la Rue; Annalise Katz-Summercorn; Sujath Abbas; Daniel Loureda; Maria O’Donovan; Ahmad Miremadi; Shalini Malhotra; Monika Tripathi; Simon Tavaré; Andy G. Lynch; Matthew Eldridge; Maria Secrier; Ginny Devonshire; Juliane Perner; Sri Ganesh Jammula; Jim Davies; Charles Crichton; Nick Carroll; Jesper Lagergren; Fuju Chang; Janine Zylstra; Vicky Goh; Francesca D. Ciccarelli

doi:10.1038/s41588-018-0331-5

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

the Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium, Alexander M. Frankell, Sri Ganesh Jammula, Xiaodun Li, Gianmarco Contino, Sarah Killcoyne, Sujath Abbas, Juliane Perner, Lawrence Bower, Ginny Devonshire, Emma Ococks, Nicola Grehan, James Mok, Maria O’Donovan, Shona MacRae, Matthew D. Eldridge, Simon Tavaré, Rebecca C. Fitzgerald, Ayesha Noorani, Paul A.W. EdwardsNicola Grehan, Barbara Nutzinger, Caitriona Hughes, Elwira Fidziukiewicz, Shona MacRae, Alex Northrop, Gianmarco Contino, Xiaodun Li, Rachel de la Rue, Annalise Katz-Summercorn, Sujath Abbas, Daniel Loureda, Maria O’Donovan, Ahmad Miremadi, Shalini Malhotra, Monika Tripathi, Simon Tavaré, Andy G. Lynch, Matthew Eldridge, Maria Secrier, Ginny Devonshire, Juliane Perner, Sri Ganesh Jammula, Jim Davies, Charles Crichton, Nick Carroll, Jesper Lagergren, Fuju Chang, Janine Zylstra, Vicky Goh, Francesca D. Ciccarelli

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144 Citations (Scopus)

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.

Original language	English
Pages (from-to)	506-516
Number of pages	11
Journal	Nature Genetics
Volume	51
Issue number	3
Early online date	4 Feb 2019
DOIs	https://doi.org/10.1038/s41588-018-0331-5
Publication status	E-pub ahead of print - 4 Feb 2019

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the Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium, Frankell, A. M., Jammula, S. G., Li, X., Contino, G., Killcoyne, S., Abbas, S., Perner, J., Bower, L., Devonshire, G., Ococks, E., Grehan, N., Mok, J., O’Donovan, M., MacRae, S., Eldridge, M. D., Tavaré, S., Fitzgerald, R. C., Noorani, A., ... Ciccarelli, F. D. (2019). The landscape of selection in 551 esophageal adenocarcinomas defines genomic biomarkers for the clinic. Nature Genetics, 51(3), 506-516. Advance online publication. https://doi.org/10.1038/s41588-018-0331-5

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title = "The landscape of selection in 551 esophageal adenocarcinomas defines genomic biomarkers for the clinic",

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.",

author = "{the Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium} and Frankell, {Alexander M.} and Jammula, {Sri Ganesh} and Xiaodun Li and Gianmarco Contino and Sarah Killcoyne and Sujath Abbas and Juliane Perner and Lawrence Bower and Ginny Devonshire and Emma Ococks and Nicola Grehan and James Mok and Maria O{\textquoteright}Donovan and Shona MacRae and Eldridge, {Matthew D.} and Simon Tavar{\'e} and Fitzgerald, {Rebecca C.} and Ayesha Noorani and Edwards, {Paul A.W.} and Nicola Grehan and Barbara Nutzinger and Caitriona Hughes and Elwira Fidziukiewicz and Shona MacRae and Alex Northrop and Gianmarco Contino and Xiaodun Li and {de la Rue}, Rachel and Annalise Katz-Summercorn and Sujath Abbas and Daniel Loureda and Maria O{\textquoteright}Donovan and Ahmad Miremadi and Shalini Malhotra and Monika Tripathi and Simon Tavar{\'e} and Lynch, {Andy G.} and Matthew Eldridge and Maria Secrier and Ginny Devonshire and Juliane Perner and Jammula, {Sri Ganesh} and Jim Davies and Charles Crichton and Nick Carroll and Jesper Lagergren and Fuju Chang and Janine Zylstra and Vicky Goh and Ciccarelli, {Francesca D.}",

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doi = "10.1038/s41588-018-0331-5",

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the Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium, Frankell, AM, Jammula, SG, Li, X, Contino, G, Killcoyne, S, Abbas, S, Perner, J, Bower, L, Devonshire, G, Ococks, E, Grehan, N, Mok, J, O’Donovan, M, MacRae, S, Eldridge, MD, Tavaré, S, Fitzgerald, RC, Noorani, A, Edwards, PAW, Grehan, N, Nutzinger, B, Hughes, C, Fidziukiewicz, E, MacRae, S, Northrop, A, Contino, G, Li, X, de la Rue, R, Katz-Summercorn, A, Abbas, S, Loureda, D, O’Donovan, M, Miremadi, A, Malhotra, S, Tripathi, M, Tavaré, S, Lynch, AG, Eldridge, M, Secrier, M, Devonshire, G, Perner, J, Jammula, SG, Davies, J, Crichton, C, Carroll, N, Lagergren, J , Chang, F , Zylstra, J , Goh, V & Ciccarelli, FD 2019, 'The landscape of selection in 551 esophageal adenocarcinomas defines genomic biomarkers for the clinic', Nature Genetics, vol. 51, no. 3, pp. 506-516. https://doi.org/10.1038/s41588-018-0331-5

TY - JOUR

T1 - The landscape of selection in 551 esophageal adenocarcinomas defines genomic biomarkers for the clinic

AU - the 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 - Lagergren, Jesper

AU - Chang, Fuju

AU - Zylstra, Janine

AU - Goh, Vicky

AU - Ciccarelli, Francesca D.

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.

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U2 - 10.1038/s41588-018-0331-5

DO - 10.1038/s41588-018-0331-5

M3 - Article

AN - SCOPUS:85061351097

SN - 1061-4036

VL - 51

SP - 506

EP - 516

JO - Nature Genetics

JF - Nature Genetics

IS - 3

ER -

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

Abstract

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