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

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

Authors:	Dhara, S.; Chhangawala, S.; Chintalapudi, H.; Askan, G.; Aveson, V.; Massa, A. L.; Zhang, L.; Torres, D.; Makohon-Moore, A. P.; Lecomte, N.; Melchor, J. P.; Bermeo, J.; Cardenas, A. 3rd; Sinha, S.; Glassman, D.; Nicolle, R.; Moffitt, R.; Yu, K. H.; Leppanen, S.; Laderman, S.; Curry, B.; Gui, J.; Balachandran, V. P.; Iacobuzio-Donahue, C.; Chandwani, R.; Leslie, C. S.; Leach, S. D.
Article Title:	Pancreatic cancer prognosis is predicted by an ATAC-array technology for assessing chromatin accessibility
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-naive 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. ATAC-seq allows for the investigation of chromatin accessibility, a feature which can have important implications for gene regulation. Here the authors present ATAC-array to assess accessibility in human tumours and based on this predict disease prognosis.
Keywords:	survival; gemcitabine; tumor; models; therapies; subtypes
Journal Title:	Nature Communications
Volume:	12
ISSN:	2041-1723
Publisher:	Nature Publishing Group
Date Published:	2021-05-24
Start Page:	3044
Language:	English
ACCESSION:	WOS:000658769300013
DOI:	10.1038/s41467-021-23237-2
PROVIDER:	wos
PMCID:	PMC8144607
PUBMED:	34031415
Notes:	Article -- Source: Wos