words) 28Recent studies indicate that pancreatic cancer expression profiles are variable and largely 29 reflect a classical or basal-type phenotype. We performed genetic sequencing, RNA-seq, and 30 histologic review of multiregion sampled pancreatic cancers and found that squamous and 31 squamoid features, indicators of poor prognosis, correlate with a "basal -like" expressional type. 32Cancers with squamous features were more likely to have truncal mutations in chromatin modifier 33 genes and intercellular heterogeneity for MYC amplification that was associated with entosis. In 34 most patients the basal phenotype coexisted with a glandular component, and phylogenetic studies 35 indicated that it arose from a subclonal population in the tumor. These data provide a unifying 36 paradigm for understanding the interrelationship of basal-type features, squamous histology, and 37 somatic mutations in chromatin modifier genes in the context of the clonal evolution of pancreatic 38 cancer. 39 40 41 4 Text: 42 Despite advances in diagnostic tools, surgery, chemotherapy and radiation therapy, pancreatic 43 ductal adenocarcinoma (PDAC) remains one of the most lethal tumor types 1 . The five-year 44 survival is less than 10% with 56,770 new cases diagnosed and 45,750 deaths estimated for 2019 45 in the United States alone 2,3 . Large scale sequencing studies have revealed the recurrent genomic 46features of this disease that target a defined number of core pathways 4-8 . In some patients a genome 47 pattern (Figure 2a). Principal component analysis using this same gene set revealed a similar 130 distribution based on morphologic features or expression subtype, whereas no relationship was 131 found for site of harvesting of each sample (primary or metastasis) ( Figure 2b). Finally, we 132 compared the morphologic features to the transcriptional subtypes of each sample analyzed for 23 133
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