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

Autor: Dhara S; Dartmouth Geisel School of Medicine and Norris Cotton Cancer Center, Hanover, NH, USA., Chhangawala S; Weill Cornell Graduate School of Medical Sciences, New York, NY, USA.; Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Chintalapudi H; Dartmouth Geisel School of Medicine and Norris Cotton Cancer Center, Hanover, NH, USA., Askan G; David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Aveson V; David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Weill Cornell Medicine, New York, NY, USA., Massa AL; Dartmouth Geisel School of Medicine and Norris Cotton Cancer Center, Hanover, NH, USA., Zhang L; David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Torres D; Dartmouth Geisel School of Medicine and Norris Cotton Cancer Center, Hanover, NH, USA., Makohon-Moore AP; David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Lecomte N; David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Melchor JP; David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Bermeo J; David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Cardenas A 3rd; David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Sinha S; David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Glassman D; David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Nicolle R; Programme Cartes d'Identité des Tumeurs, Ligue Nationale Contre Le Cancer, Paris, France., Moffitt R; Stony Brook University, Stony Brook, NY, USA., Yu KH; David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Leppanen S; Agilent Technologies Inc., Santa Clara, CA, USA., Laderman S; Agilent Technologies Inc., Santa Clara, CA, USA., Curry B; Agilent Technologies Inc., Santa Clara, CA, USA., Gui J; Dartmouth Geisel School of Medicine and Norris Cotton Cancer Center, Hanover, NH, USA., Balachandran VP; David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Iacobuzio-Donahue C; David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Chandwani R; Weill Cornell Medicine, New York, NY, USA., Leslie CS; Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. cleslie@cbio.mskcc.org., Leach SD; Dartmouth Geisel School of Medicine and Norris Cotton Cancer Center, Hanover, NH, USA. sdl@dartmouth.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2021 May 24; Vol. 12 (1), pp. 3044. Date of Electronic Publication: 2021 May 24.
DOI: 10.1038/s41467-021-23237-2
Abstrakt: 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.
Databáze: MEDLINE
Externí odkaz: