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

Abstract

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 wellcharacterized 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.

Proteogenomic characterization of pancreatic ductal adenocarcinoma

“…Consistent with a previous report (Cancer Genome Atlas Research Network, 2017), some of these molecular classifications overlapped significantly, such as ''ADEX'' (Bailey) and ''exocrine-like'' (Collisson), ''Classical (Collisson)'' and ''pancreatic progenitor'' (Bailey), and ''squamous'' (Bailey), ''quasimesenchymal'' (Collisson) and ''basal-like'' (Moffitt) (p < 0.0001, Fisher's exact test). Notably, five adenosquamous carcinoma samples in our cohort were classified into ''squamous'' (Bailey), ''quasimesenchymal'' (Collisson), or ''basal-like'' (Moffit) groups, in line with the understanding for this histological pancreatic cancer subtype (Boecker et al, 2020;Lenkiewicz et al, 2020;Moffitt et al, 2015). Non-negative matrix factorization (NMF)-based proteogenomics subtyping using multiomics data from all 140 tumors revealed four clusters with significant overlap with RNA subtypes (Figures S7B and S7C; Table S7A).…”

Morphologic and Molecular Landscape of Pancreatic Cancer Variants as the Basis of New Therapeutic Strategies for Precision Oncology

“…In particular, mutations in the histone-lysine N-methyltransferase 2 (KMT2)C and KMT2D, the ATP-dependent chromatin remodeler SMARCA4, and lysine demethylase (KDM)6 are reported in 7%, 5%, and 5% of the patients, respectively [85]. A recent manuscript by Lenkiewicz and collaborators showed mutations also in the KDM3 [86]. Alongside confirming the alterations in chromatin regulatory genes, this manuscript is very relevant for two critical aspects: (I) it confirms that ASC evolves from the same lineage as PDAC, as they share canonical mutations in KRAS, TP53, CDKN2A, SMAD4 and MYC; and (II) it demonstrates that the genetic characterization of the PDAC variants is crucial in defining new therapeutic intervention strategies.…”

“…By ATAC-seq in KPC mouse model, the authors define the status of the nuclear receptor ROR-γ (RORC)-a nuclear receptor hormone involved in the Th-17-dependent inflammatory cytokines release-as a specific feature of ASC; the authors also demonstrated the co-occurrence of genetic alterations in KRAS and fibroblast growth factor receptor (FGFR). From an interesting translational point of view, the authors showed that organoids RORC + /FGFR-ERLIN2 fusion/KRAS G12V are more sensitive to the single-agent FGFR inhibitor infigratinib [86].…”

Tracing tumor evolution and subtype specification in pancreatic cancer

“…However, within the exocrine pancreas, multiple other forms of malignancies can occur. This includes adenosquamous carcinoma of pancreas (ASCP), an aggressive sub-type of PDAC that has the worst clinical prognosis [4][5][6] ; acinar cell carcinoma (ACC), which accounts for 15% of all childhood pancreatic cancers and is only moderately responsive to chemotherapies 7 ; and the highly aggressive anaplastic tumors, characterized by their undifferentiated state 8 . While originally considered rare, recent studies have indicated that a substantially higher fraction of conventional PDAC (18%) harbors admixed adenosquamous features than was previously recognized 9 .…”

“…Here we report a new mouse model in which targeting oncogenic Myc to adult pancreatic precursor cells triggered the development of PDAC, ASCP, ACC and anaplastic tumors. Our current model is particularly exciting and highly relevant to human disease, as deregulated expression or amplification of c-MYC is associated with higher incidence of ASCP (47%) and ACCs (54% in pure and up to 100% in mixed ACCs) in human pancreatic patients, irrespective of KRAS mutation status 5,15,16 . This work provides an exciting new model for multiple subtypes of pancreatic cancer, and a unique opportunity to trace, at single cell resolution, the origins of the pre-malignant state and its evolution to distinct lethal malignancies.…”