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Exome and whole genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexity

ABSTRACT: The incidence of esophageal adenocarcinoma (EAC) has risen 600% over the last 30 years. With an extremely poor five-year survival rate of only 15%, identification of new therapeutic targets for EAC is of great importance. Here, we analyze the mutation spectra from the whole exome sequencing of 149 EAC tumors/normal pairs, 15 of which have also been subjected to whole genome sequencing. We identify a novel mutational signature in EACs defined by a high prevalence of A to C transversions at Ap*A dinucleotides. Statistical analysis of the exome data identified 26 genes that are mutated at a significant frequency. Of these 26 genes, only four (TP53, CDKN2A, SMAD4, and PIK3CA) have been previously implicated in EAC. The novel significantly mutated genes include several chromatin modifying factors and candidate contributors to EAC: SPG20, TLR4, ELMO1, and DOCK2. Notably, functional analyses of EAC-derived mutations in ELMO1 increase cellular invasion. Therefore, we suggest a new hypothesis about the potential activation of the RAC1 pathway to be a contributor to EAC tumorigenesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE42363 | GEO | 2013/02/11

SECONDARY ACCESSION(S): PRJNA181161

REPOSITORIES: GEO

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Project description:Rheumatoid arthritis is an inflammatory disease of the synovial joints that affects ~1% of the human population, with severe distress due to progressive joint inflammation and deformation. When addressing the links between specific components of the apoptotic cell clearance machinery and human disease, we noted a correlation between single nucleotide polymorphisms (SNPs) in ELMO1, DOCK2, and RAC1 genes and rheumatoid arthritis. ELMO1 is a cytoplasmic adapter protein that associates with DOCK2 and RAC1 to promote cytoskeletal reorganization needed for apoptotic cell uptake by phagocytes. We initially hypothesized that, since ELMO1 is linked to apoptotic cell clearance, loss of ELMO1 would lead to increased inflammation in arthritis. Contrary to the accumulation of apoptotic cells and greater disease severity that we predicted, we observed significantly reduced joint inflammation in two models of arthritis in mice lacking ELMO1. Using genetic and cell biological approaches in vivo and ex vivo, we determined that ELMO1 deficiency significantly reduces neutrophil recruitment to inflamed joints, but does not result in general inhibition of inflammatory responses. Through proteomic analyses, we find that ELMO1 protein associates with cellular receptors that contribute to neutrophil function in arthritis, and regulates C5a and LTB4 receptor-mediated activation and early neutrophil recruitment to the joints. Neutrophil-specific transcriptomics show that ELMO1 modulates neutrophil-specific gene expression that includes genes with known linkages to human arthritis. Finally, neutrophils from the peripheral blood of human donors that carry the SNP in ELMO1 associated with arthritis display increased migratory capacity, whereas ELMO1 knockdown reduces human neutrophil migration to LTB4. These data identify key ‘non-canonical’ roles for engulfment machinery components in arthritis, and ELMO1 as an important regulator of specific neutrophil receptors and signaling linked to arthritis.

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Exome and whole genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexity

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