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

Research output: Contribution to journalArticlepeer-review

Standard

The landscape of selection in 551 esophageal adenocarcinomas defines genomic biomarkers for the clinic. / Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium ; Contino, Gianmarco.

In: Nature Genetics, Vol. 51, No. 3, 03.2019, p. 506-516.

Research output: Contribution to journalArticlepeer-review

Harvard

Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium & Contino, G 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

APA

Vancouver

Author

Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium ; Contino, Gianmarco. / The landscape of selection in 551 esophageal adenocarcinomas defines genomic biomarkers for the clinic. In: Nature Genetics. 2019 ; Vol. 51, No. 3. pp. 506-516.

Bibtex

@article{78c4fefb56194b8e84fbaf124ded3350,
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.",
keywords = "Adenocarcinoma/genetics, Biomarkers, Tumor/genetics, Cohort Studies, DNA Copy Number Variations/genetics, Esophageal Neoplasms/genetics, Exome/genetics, Female, Gene Expression Profiling/methods, Gene Expression Regulation, Neoplastic/genetics, Genomics/methods, Humans, Male, Mutation/genetics",
author = "{Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium} and Frankell, {Alexander M} and SriGanesh Jammula 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'Donovan and Shona MacRae and Eldridge, {Matthew D} and Simon Tavar{\'e} and Fitzgerald, {Rebecca C}",
year = "2019",
month = mar,
doi = "10.1038/s41588-018-0331-5",
language = "English",
volume = "51",
pages = "506--516",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "3",

}

RIS

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, SriGanesh

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

PY - 2019/3

Y1 - 2019/3

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.

KW - Adenocarcinoma/genetics

KW - Biomarkers, Tumor/genetics

KW - Cohort Studies

KW - DNA Copy Number Variations/genetics

KW - Esophageal Neoplasms/genetics

KW - Exome/genetics

KW - Female

KW - Gene Expression Profiling/methods

KW - Gene Expression Regulation, Neoplastic/genetics

KW - Genomics/methods

KW - Humans

KW - Male

KW - Mutation/genetics

UR - https://www.repository.cam.ac.uk/handle/1810/297101

U2 - 10.1038/s41588-018-0331-5

DO - 10.1038/s41588-018-0331-5

M3 - Article

C2 - 30718927

VL - 51

SP - 506

EP - 516

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 3

ER -