Comprehensive DNA Methylation Analysis Indicates That Pancreatic Intraepithelial Neoplasia Lesions Are Acinar-Derived and Epigenetically Primed for Carcinogenesis

Author:

Lo Emily K.W.12ORCID,Mears Brian M.1ORCID,Maurer H. Carlo34ORCID,Idrizi Adrian1ORCID,Hansen Kasper D.156ORCID,Thompson Elizabeth D.7ORCID,Hruban Ralph H.7ORCID,Olive Kenneth P.48ORCID,Feinberg Andrew P.12910ORCID

Affiliation:

1. 1Center for Epigenetics, Johns Hopkins University School of Medicine, Baltimore, Maryland.

2. 2Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland.

3. 3Department of Internal Medicine II, Klinikum Rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany.

4. 4Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York.

5. 5Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.

6. 6McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland.

7. 7Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, Baltimore, Maryland.

8. 8Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York.

9. 9Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland.

10. 10Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Maryland.

Abstract

AbstractPancreatic ductal adenocarcinoma (PDAC) is believed to arise from the accumulation of a series of somatic mutations and is also frequently associated with pancreatic intraepithelial neoplasia (PanIN) lesions. However, there is still debate as to whether the cell type-of-origin of PanINs and PDACs in humans is acinar or ductal. As cell type identity is maintained epigenetically, DNA methylation changes during pancreatic neoplasia can provide a compelling perspective to examine this question. Here, we performed laser-capture microdissection on surgically resected specimens from 18 patients to isolate, with high purity, DNA for whole-genome bisulfite sequencing from four relevant cell types: acini, nonneoplastic ducts, PanIN lesions, and PDAC lesions. Differentially methylated regions (DMR) were identified using two complementary analytical approaches: bsseq, which identifies any DMRs but is particularly useful for large block-like DMRs, and informME, which profiles the potential energy landscape across the genome and is particularly useful for identifying differential methylation entropy. Both global methylation profiles and block DMRs clearly implicated an acinar origin for PanINs. At the gene level, PanIN lesions exhibited an intermediate acinar-ductal phenotype resembling acinar-to-ductal metaplasia. In 97.6% of PanIN-specific DMRs, PanIN lesions had an intermediate methylation level between normal and PDAC, which suggests from an information theory perspective that PanIN lesions are epigenetically primed to progress to PDAC. Thus, epigenomic analysis complements histopathology to define molecular progression toward PDAC. The shared epigenetic lineage between PanIN and PDAC lesions could provide an opportunity for prevention by targeting aberrantly methylated progression-related genes.Significance:Analysis of DNA methylation landscapes provides insights into the cell-of-origin of PanIN lesions, clarifies the role of PanIN lesions as metaplastic precursors to human PDAC, and suggests potential targets for chemoprevention.

Funder

National Cancer Institute

National Human Genome Research Institute

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology

Reference74 articles.

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