Identification of distinct mutational patterns and new driver genes in oesophageal squamous cell carcinomas and adenocarcinomas

Abstract

ObjectivesOesophageal squamous cell carcinoma (OSCC) and adenocarcinoma (OAC) are distinct cancers in terms of a number of clinical and epidemiological characteristics, complicating the design of clinical trials and biomarker developments. We analysed 1048 oesophageal tumour-germline pairs from both subtypes, to characterise their genomic features, and biological and clinical significance.DesignPreviously exome-sequenced samples were re-analysed to identify significantly mutated genes (SMGs) and mutational signatures. The biological functions of novel SMGs were investigated using cell line and xenograft models. We further performed whole-genome bisulfite sequencing and chromatin immunoprecipitation (ChIP)-seq to characterise epigenetic alterations.ResultsOSCC and OAC displayed nearly mutually exclusive sets of driver genes, indicating that they follow independent developmental paths. The combined sample size allowed the statistical identification of a number of novel subtype-specific SMGs, mutational signatures and prognostic biomarkers. Particularly, we identified a novel mutational signature similar to Catalogue Of Somatic Mutations In Cancer (COSMIC)signature 16, which has prognostic value in OSCC. Two newly discovered SMGs, CUL3 and ZFP36L2, were validated as important tumour-suppressors specific to the OSCC subtype. We further identified their additional loss-of-function mechanisms. CUL3 was homozygously deleted specifically in OSCC and other squamous cell cancers (SCCs). Notably, ZFP36L2 is associated with super-enhancer in healthy oesophageal mucosa; DNA hypermethylation in its super-enhancer reduced active histone markers in squamous cancer cells, suggesting an epigenetic inactivation of a super-enhancer-associated SCC suppressor.ConclusionsThese data comprehensively contrast differences between OSCC and OAC at both genomic and epigenomic levels, and reveal novel molecular features for further delineating the pathophysiological mechanisms and treatment strategies for these cancers.

The landscape of selection in 551 Esophageal Adenocarcinomas defines genomic biomarkers for the clinic

“…The simplest of these features is the tendency of a mutation to co-occur with other mutations in the same gene at a high frequency, as detected by MutsigCV 9 . MutsigCV has been applied on several occasions to EAC cohorts 6,10,11 and has identified ten known cancer genes as high confidence EAC drivers (TP53, CDKN2A, SMAD4, ARID1A, ERBB2, KRAS, PIK3CA, SMARCA4, CTNNB1 and FBXW7). Analysis of the non-coding genome has been performed by the PCAWG ICGC analysis and identified a significantly mutated enhancer associated with TP53TG1 12 .…”

TP63, SOX2 and KLF5 Establish Core Regulatory Circuitry and Construct Cancer Specific Epigenome in Esophageal Squamous Cell Carcinoma

“…ESCC is common (more than 400,000 cases each year) and aggressive malignancy (causing almost 300,000 deaths per year), with a 5-year survival rate less than 20% Enzinger and Mayer, 2003). Unfortunately, genome-guided therapeutic strategy is still unavailable for ESCC patients, although ESCC genomic abnormalities have been comprehensively characterized and established (Cancer Genome Atlas Research et al, 2017;Gao et al, 2014;Lin et al, 2018a;Lin et al, 2014;Lin et al, 2018b;Liu et al, 2017;Song et al, 2014). In addition, the high-degree genomic heterogeneity of this cancer further limits application of mutational-targeted therapy.…”

Molecular landscape of esophageal cancer: implications for early detection and personalized therapy

“…Other studies with a genome‐wide approach also supported the TCGARN findings with a larger sample size showing contrasting differences between ESCC and EAC both at genomic and epigenomic levels, and revealed novel molecular features for further delineating these cancers. They also reported two significantly mutated genes CUL3 and ZFP36L2 , which were functionally validated as important tumor suppressors specific to the ESCC subtype . In a separate study, WES of ESCC and EAC exhibited substantial disparity in the spectrum of mutations, with more indels and NOTCH1 loss‐of‐function mutations specific to ESCCs.…”

“…They also reported two significantly mutated genes CUL3 and ZFP36L2, which were functionally validated as important tumor suppressors specific to the ESCC subtype. 24 In a separate study, WES of ESCC and EAC exhibited substantial disparity in the spectrum of mutations, with more indels and NOTCH1 loss-of-function mutations specific to ESCCs. They also identified the overlapping mutations between EACs and matched BE.…”