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

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. We applied DNA content based flow sorting to isolate the nuclei of clonal populations from ASCP tumor biopsies and patient derived xenografts (PDXs). We coupled this strategy with oligonucleotide array CGH (aCGH) and next generation sequencing, thereby obtaining high definition genomic profiles of clonal populations from each tumor. Flow sorted PDXs were used for ATAC-seq analyses of both ASCP and PDAC genomes. Response to FGFR inhibition was assesed with ASCP organoid models.