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

Journal article

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.

Authors: Frankell, AM; Jammula, S; Li, X; Contino, G; Killcoyne, S

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Springer Nature
• Journal: Nature Genetics
• Volume: 51
• Issue: 3
• Pages: 506-516
• Publication date: 2019-02-04
• Acceptance date: 2018-12-10
• DOI: 10.1038/s41588-018-0331-5
• EISSN: 1546-1718
• ISSN: 1061-4036
• Pmid: 30718927
• Language: English
• Keywords: Female; Humans; Biomarkers, Tumor; Esophageal Neoplasms; Genomics; Mutation; DNA Copy Number Variations; Exome; Gene Expression Regulation, Neoplastic; Cohort Studies; Male; Gene Expression Profiling; Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium; Adenocarcinoma; FT