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Nat Commun. 2018 May 17;9(1):1978. doi: 10.1038/s41467-018-04383-6.

Distinct epigenetic landscapes underlie the pathobiology of pancreatic cancer subtypes.

Author information

1
Division of Research, Department of Surgery, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, Wisconsin, 53226, USA. glomberk@mcw.edu.
2
Programme Cartes d'Identité des Tumeurs (CIT), Ligue Nationale Contre Le Cancer, 14 rue Corvisart, Paris, 75013, France.
3
Division of Biomedical Statistics and Informatics, Department of Health Science Research, Mayo Clinic, 200 First Street SW, Rochester, Minnesota, 55905, USA.
4
Genomic Sciences and Precision Medicine Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, Wisconsin, 53226, USA.
5
Epigenomics Program, Center for Individualized Medicine, Mayo Clinic, 200 First Street SW, Rochester, Minnesota, 55905, USA.
6
Department of Physiology and Biomedical Engineering, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
7
Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, 163 Avenue de Luminy, Marseille, 13288, France.
8
Hôpital Nord, Chemin des Bourrely, Marseille, 13015, France.
9
Institut Paoli-Calmettes, 232 Boulevard Sainte Marguerite, Marseille, 13009, France.
10
Hôpital de la Timone, 264 rue Saint-Pierre, Marseille, 13385, France.
11
Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, 163 Avenue de Luminy, Marseille, 13288, France. juan.iovanna@inserm.fr.
12
Division of Research, Department of Surgery, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, Wisconsin, 53226, USA. rurrutia@mcw.edu.
13
Genomic Sciences and Precision Medicine Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, Wisconsin, 53226, USA. rurrutia@mcw.edu.
14
Epigenomics Program, Center for Individualized Medicine, Mayo Clinic, 200 First Street SW, Rochester, Minnesota, 55905, USA. rurrutia@mcw.edu.

Abstract

Recent studies have offered ample insight into genome-wide expression patterns to define pancreatic ductal adenocarcinoma (PDAC) subtypes, although there remains a lack of knowledge regarding the underlying epigenomics of PDAC. Here we perform multi-parametric integrative analyses of chromatin immunoprecipitation-sequencing (ChIP-seq) on multiple histone modifications, RNA-sequencing (RNA-seq), and DNA methylation to define epigenomic landscapes for PDAC subtypes, which can predict their relative aggressiveness and survival. Moreover, we describe the state of promoters, enhancers, super-enhancers, euchromatic, and heterochromatic regions for each subtype. Further analyses indicate that the distinct epigenomic landscapes are regulated by different membrane-to-nucleus pathways. Inactivation of a basal-specific super-enhancer associated pathway reveals the existence of plasticity between subtypes. Thus, our study provides new insight into the epigenetic landscapes associated with the heterogeneity of PDAC, thereby increasing our mechanistic understanding of this disease, as well as offering potential new markers and therapeutic targets.

PMID:
29773832
PMCID:
PMC5958058
DOI:
10.1038/s41467-018-04383-6
[Indexed for MEDLINE]
Free PMC Article

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