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Sequencing data for oesophageal and related samples - eo_paper_ctdna_release - samples

ABSTRACT: Data supporting: Ã¢Â€ÂœLongitudinal tracking of 97 esophageal adenocarcinomas (EAC) using liquid biopsy sampling.Ã¢Â€Â Ococks, Frankell, Masque Soler et al. ctDNA (BAM files) 333 samples

PROVIDER: EGAD00001006373 | EGA |

REPOSITORIES: EGA

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Project description:A complete response following neoadjuvant therapy occurs only in a fraction of patients with esophageal adenocarcinoma (EAC). Further targeted treatment options are needed to improve treatment response and patient survival. Mouse double minute 2 homolog (MDM2) is a known oncogene. Its upregulation results in a more aggressive cancer phenotype. It is currently under investigation as a potential therapeutic target. However, initial findings have not been groundbreaking. Therefore, this study aimed to identify further potential therapeutic targets in the subtype of MDM2-amplified EAC.Methods: We screened 656 patients with operable esophageal adenocarcinoma for their MDM2-amplification status using Fluorescence in situ Hybridization (FISH). 57 tumors (8.7%) were MDM2-amplified. The proteome of 35 MDM2-amplified and 37 non-amplified tumors was analyzed using mass spectrometry. 22.2% of the included patients were primarily resected, and 77.8% were neoadjuvant treated.Results: The comparison of MDM2-amplified and non-amplified tumors revealed various differently expressed proteins and pathways. Hornerin, Bystin, and subtypes of keratins (KRT1, KRT2, KRT9, KRT10) were significantly downregulated. Whereas Choline transporter-like protein 2 (CTL2), Cullin-associated NEDD8-dissociated protein 1 (CAND1), FAD- and RhoGTPase-binding protein 1 (FARP1), and Contactin 1 were upregulated in MDM2-amplified EAC. Enrichment analyses revealed that MDM2-amplified esophageal adenocarcinomas showed a more pronounced immunosuppressive phenotype due to the downregulation of interferon signaling pathways and antigen presentation. Furthermore, distinct metabolic pathways like carbon, propanoate, tryptophan, and tyrosine metabolism were upregulated in MDM2-amplified tumors.Conclusion:In this study, we investigated the whole proteome of MDM2-amplified compared to non-amplified esophageal adenocarcinomas. We described numerous potential future therapeutic targets, suggesting patients with MDM2-amplified tumors could potentially benefit from, exemplary, Mitogen-activated protein kinase kinase (MEK) inhibitors or tryptophan metabolism inhibitors. Future mechanistic studies are needed to validate these findings.

Project description:We applied whole-genome single nucleotide polymorphism (SNP) arrays to define a comprehensive genetic profile of 23 esophageal adenocarcinoma (EAC) primary tumor biopsies based on loss of heterozygosity (LOH) and DNA copy number changes. Alterations were common, averaging 97 (range 23-208) per tumor. LOH and gains averaged 33 (range 3-83) and 31 (range 11-73) per tumor, respectively. Copy neutral LOH events averaged 27 (range 7-57) per EAC. We noted 126 homozygous deletions (HDs) across the EAC panel (range 0-11 in individual tumors). Frequent HDs within FHIT (17/23), WWOX (8/23) and DMD (6/23) suggest a role for common fragile sites or genomic instability in EAC etiology. HDs were also noted for known tumor suppressor genes (TSGs) including: CDKN2A, CDKN2B, SMAD4 and GALR1, and identified PDE4D and MGC48628 as potentially novel TSGs. All tumors showed LOH for most of chromosome 17p, suggesting that TSGs other than TP53 maybe targeted. Frequent gains were noted around MYC (13/23), BCL9 (12/23), CTAGE1 (14/23) and ZNF217 (12/23). Thus, we have confirmed previous reports indicating frequent changes to FHIT, CDKN2A, TP53 and MYC in EAC and identified additional genes of interest. Meta analysis of previous genome-wide EAC studies together with the data presented here, highlighted consistent regions of gain on 8q, 18q and 20q, and multiple LOH regions on 4q, 5q, 17p and 18q, suggesting that more than one gene may be targeted on each of these chromosome arms. The focal gains and deletions documented here are a step towards identifying the key genes involved in EAC development. Keywords: High Density SNP array Here we use Illumina 317K whole-genome single-nucleotide polymorphism arrays to define a comprehensive allelotype of melanoma based on loss of heterozygosity (LOH) and copy number changes in a panel of 23 esophageal adenocarcinoma (EAC) primary tumor biopsies. Each EAC was paired to normal squamous biopsy from 40328 (GSM266078) to generate the log_R_ratio.

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Sequencing data for oesophageal and related samples - eo_paper_ctdna_release - samples

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