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

Abstract

Data availability. The WGS and RNA expression data can be found at the European Genome-phenome Archive (EGA) under accessions EGAD00001004417 and EGAD00001004423, respectively. Code availability. Code associated with the analysis is available upon request. Ethics. The study was registered (UKCRNID 8880), approved by the Institutional Ethics Committees (REC 07/H0305/52 and 10/ H0305/1), and all subjects gave individual informed consent. Reporting summary. Additional information is included in the Life Sciences Reporting Summary, which details exact software and biological materials used and efforts made to ensure reproducibility of results. Author contributions RCF and AMF conceived the overall study. AMF and SJ analyzed the genomic data and performed statistical analyses. RCF, AMF and XL designed the experiments. AMF, XL and JM performed the experiments. GC contributed to the structural variant analysis and data visualization. SK helped compile the clinical data and aided statistical analyses. JP and SA produced and QC'ed the RNA-seq data. EO aided the whole genome sequencing of EAC cell lines. SM and NG coordinated the clinical centres and were responsible for sample collections. ME benchmarked our mutation calling pipelines. MO led the pathological sample QC for sequencing. LB and GD constructed and managed the sequencing alignment and variant calling pipelines. RCF and ST supervised the research. RCF and ST obtained funding. AMF and RCF wrote the manuscript. All authors approved the manuscript.

Identification of a primitive intestinal transcription factor network shared between esophageal adenocarcinoma and its precancerous precursor state

“…One reason for the poor prognosis is the lack of tailored therapies due to the relative paucity of molecular knowledge compared to other cancers. We are beginning to understand the molecular mechanisms underpinning this disease, chiefly through genomic sequencing studies, which have revealed multiple genes that are recurrently mutated in EAC (Dulak et al 2013;Weaver et al 2014;Ross-Innes et al 2015;Frankell et al 2019). However, with the exception of TP53, the overall incidence of mutations in individual genes is low.…”

The potential and challenges of patient-derived organoids in guiding the multimodality treatment of upper gastrointestinal malignancies

“…Over the last few years, the genomic tumour landscape was extensively studied with high-throughput sequencing methods such as whole-genome/exome sequencing, DNA methylation-based profiling, mRNA sequencing and analysis of somatic copy-number alterations for either oesophageal tumours [10,11], gastric carcinoma [12,13] or comparing tumours spanning the entire gastrointestinal tract (GI) [14]. Comparison of all gastrointestinal adenocarcinomas (GIACs) to other cancer types, including lung and breast, indicate that GIACs constitute a unique entity with specific mutations (e.g.…”

“…OSCC have a higher resemblance to head and neck squamous cell carcinoma [11], whereas OAC and GAC cluster together [11,14]. An independent study focusing on 551 OACs [10] expanded the list of potential driver mutations, which are located in either coding genes or noncoding elements, such as promoters and enhancers. Similar to other studies, massive chromosomal amplifications and deletions are observed, but interestingly only a few of them are predicted to cause significant gene expression changes.…”

“…Historically, human cancer-derived two-dimensional (2D) cell lines are the most widely used model for studying human tumour features, such as the cell line SKGT4 for oesophageal or AGS for gastric cancer. These cell lines are still frequently used as a model to test drug applicability [10,20], since they have fast proliferation rates, and are easy to handle and to genetically modify. However, these cell lines are generally derived from single cancerogenic subclones, which do not recapitulate the heterogeneity of original tumours [21].…”

Extreme intratumour heterogeneity and driver evolution in mismatch repair deficient gastro-oesophageal cancer

“…Gastro-oesophageal adenocarcinomas (GOAs) are one of the commonest causes of cancer related mortality worldwide 1 . Microsatellite instable (MSI) and DNA mismatch repair deficient (dMMR) cancers are a distinct subtype of GOAs with a reported prevalence of up to ~20% [2][3][4] in the stomach and gastro-oesophageal junction but which are rare in the oesophagus 5,6 . dMMR results from genetic inactivation of MLH1, MSH2, MSH6 or PMS2 or methylation of MLH1.…”