Pancreatic cancer prognosis is predicted by an ATAC-array technology for assessing chromatin accessibility

Nat Commun. 2021 May 24;12(1):3044. doi: 10.1038/s41467-021-23237-2.

Abstract

Unlike other malignancies, therapeutic options in pancreatic ductal adenocarcinoma (PDAC) are largely limited to cytotoxic chemotherapy without the benefit of molecular markers predicting response. Here we report tumor-cell-intrinsic chromatin accessibility patterns of treatment-naïve surgically resected PDAC tumors that were subsequently treated with (Gem)/Abraxane adjuvant chemotherapy. By ATAC-seq analyses of EpCAM+ PDAC malignant epithelial cells sorted from 54 freshly resected human tumors, we show here the discovery of a signature of 1092 chromatin loci displaying differential accessibility between patients with disease free survival (DFS) < 1 year and patients with DFS > 1 year. Analyzing transcription factor (TF) binding motifs within these loci, we identify two TFs (ZKSCAN1 and HNF1b) displaying differential nuclear localization between patients with short vs. long DFS. We further develop a chromatin accessibility microarray methodology termed "ATAC-array", an easy-to-use platform obviating the time and cost of next generation sequencing. Applying this methodology to the original ATAC-seq libraries as well as independent libraries generated from patient-derived organoids, we validate ATAC-array technology in both the original ATAC-seq cohort as well as in an independent validation cohort. We conclude that PDAC prognosis can be predicted by ATAC-array, which represents a low-cost, clinically feasible technology for assessing chromatin accessibility profiles.

Publication types

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

MeSH terms

  • Biomarkers, Tumor
  • Carcinoma, Pancreatic Ductal / diagnosis
  • Carcinoma, Pancreatic Ductal / genetics
  • Carcinoma, Pancreatic Ductal / metabolism
  • Cell Nucleus
  • Chromatin Immunoprecipitation Sequencing / methods*
  • Chromatin*
  • Hepatocyte Nuclear Factor 1-beta / genetics
  • High-Throughput Nucleotide Sequencing / methods
  • Humans
  • Kruppel-Like Transcription Factors / genetics
  • Pancreatic Neoplasms / diagnosis*
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / metabolism
  • Prognosis
  • Transcription Factors
  • Transcriptome

Substances

  • Biomarkers, Tumor
  • Chromatin
  • HNF1B protein, human
  • Kruppel-Like Transcription Factors
  • Transcription Factors
  • ZKSCAN1 protein, human
  • Hepatocyte Nuclear Factor 1-beta