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Genomic Landscape and Therapeutic Targets of Adenosquamous Carcinoma of the Pancreas

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE143565 | GEO | 2020/01/14

REPOSITORIES: GEO

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Genomic Landscape and Therapeutic Targets of Adenosquamous Carcinoma of the Pancreas [CGH Microarray]

Project description:We applied DNA content flow cytometry to a series of adenosquamous cancer of the pancreas (ASCP) tumor samples and patient derived xenografts (PDXs). We interrogated purified sorted tumor fractions from each sample with whole genome copy number variant (CNV) and whole exome sequencing (WES) analyses. These identified a variety of somatic genomic lesions targeting chromatin regulators in ASCP genomes that were superimposed on well characterized genomic lesions including mutations in KRAS and TP53, homozygous deletion of CDKN2A, and amplification of c-MYC, that are common in PDACs. Furthermore, a comparison of ATAC-seq profiles of ASCP and pancreatic ductal adenocarcinoma (PDAC) genomes using flow sorted PDX models distinguished genes with accessible chromatin in ASCP genomes including the lysine methyltransferase SMYD2, the pancreatic cancer stem cell driver RORγ, and a FGFR1-ERLIN2 fusion associated with focal CNVs in both genes. Organoids derived from these models were used to screen compounds of interest. Notably a FGFR inhibitor had significant activity against the FGFR1-ERLIN2 fusion positive PDX.

2020-01-08 | GSE143256 | GEO

Genomic Landscape and Therapeutic Targets of Adenosquamous Carcinoma of the Pancreas [ATAC-seq]

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Genomic and Epigenomic Landscaping Defines New Therapeutic Targets for Adenosquamous Carcinoma of the Pancreas.

Project description:Adenosquamous cancer of the pancreas (ASCP) is a subtype of pancreatic cancer that has a worse prognosis and greater metastatic potential than the more common pancreatic ductal adenocarcinoma (PDAC) subtype. To distinguish the genomic landscape of ASCP and identify actionable targets for this lethal cancer, we applied DNA content flow cytometry to a series of 15 tumor samples including five patient-derived xenografts (PDX). We interrogated purified sorted tumor fractions from these samples with whole-genome copy-number variant (CNV), whole-exome sequencing, and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) analyses. These identified a variety of somatic genomic lesions targeting chromatin regulators in ASCP genomes that were superimposed on well-characterized genomic lesions including mutations in TP53 (87%) and KRAS (73%), amplification of MYC (47%), and homozygous deletion of CDKN2A (40%) that are common in PDACs. Furthermore, a comparison of ATAC-seq profiles of three ASCP and three PDAC genomes using flow-sorted PDX models identified genes with accessible chromatin unique to the ASCP genomes, including the lysine methyltransferase SMYD2 and the pancreatic cancer stem cell regulator RORC in all three ASCPs, and a FGFR1-ERLIN2 fusion associated with focal CNVs in both genes in a single ASCP. Finally, we demonstrate significant activity of a pan FGFR inhibitor against organoids derived from the FGFR1-ERLIN2 fusion-positive ASCP PDX model. Our results suggest that the genomic and epigenomic landscape of ASCP provide new strategies for targeting this aggressive subtype of pancreatic cancer. SIGNIFICANCE: These data provide a unique description of the ASCP genomic and epigenomic landscape and identify candidate therapeutic targets for this dismal cancer.

| S-EPMC7906529 | biostudies-literature

Genomic Landscape and Therapeutic Targets of Adenosquamous Carcinoma of the Pancreas

Project description:Genomic Landscape and Therapeutic Targets of Adenosquamous Carcinoma of the Pancreas

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Genomic Landscape and Therapeutic Targets of Adenosquamous Carcinoma of the Pancreas [ATAC-seq]

Project description:Genomic Landscape and Therapeutic Targets of Adenosquamous Carcinoma of the Pancreas [ATAC-seq]

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Genomic Landscape and Therapeutic Targets of Adenosquamous Carcinoma of the Pancreas [CGH Microarray]

Project description:Genomic Landscape and Therapeutic Targets of Adenosquamous Carcinoma of the Pancreas [CGH Microarray]

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Project description:This SuperSeries is composed of the SubSeries listed below.

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Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

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