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

Cancer Res. 2020 Oct 15;80(20):4324-4334. doi: 10.1158/0008-5472.CAN-20-0078. Epub 2020 Sep 14.

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 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Adenosquamous / drug therapy
  • Carcinoma, Adenosquamous / genetics*
  • Carcinoma, Adenosquamous / pathology
  • Carcinoma, Pancreatic Ductal / genetics
  • Carcinoma, Pancreatic Ductal / pathology
  • Chromatin / genetics*
  • Chromatin / metabolism
  • Epigenome*
  • Humans
  • Mutation*
  • Organoids
  • Pancreatic Neoplasms / drug therapy
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / pathology
  • Proto-Oncogene Proteins p21(ras)* / genetics
  • Receptor, Fibroblast Growth Factor, Type 1 / antagonists & inhibitors
  • Receptor, Fibroblast Growth Factor, Type 1 / genetics
  • Single-Cell Analysis
  • Smad4 Protein / genetics
  • Whole Exome Sequencing

Substances

  • Chromatin
  • KRAS protein, human
  • SMAD4 protein, human
  • Smad4 Protein
  • FGFR1 protein, human
  • Receptor, Fibroblast Growth Factor, Type 1
  • Proto-Oncogene Proteins p21(ras)