DNA Methylation-Derived Immune Cell Profiles, CpG Markers of Inflammation, and Pancreatic Cancer Risk

• Type of Material: Article
• Authors: Dominique S. Michaud, Tufts University; Mengyuan Ruan, Tufts University; Devin C. Koestler, University of Kansas; Lola Alonso, Spanish National Cancer Center; Esther Molina-Montes, Spanish National Cancer Center; Dong Pei, University of Kansas; Carmen Marsit, Emory University; Immaculata De Vivo, Brigham & Womens Hospital; Núria Malats, Spanish National Cancer Center; Karl T. Kelsey, Brown University
• Language: English
• Date: 2020-08-01
• Publisher: American Association for Cancer Research (AACR)
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2020 American Association for Cancer Research.
• Final Published Version (URL): http://dx.doi.org/10.1158/1055-9965.EPI-20-0378
• Title of Journal or Parent Work: Cancer Epidemiology, Biomarkers & Prevention
• Volume: 29
• Issue: 8
• Start Page: 1577
• End Page: 1585
• Grant/Funding Information: The research reported in this publication was primarily supported by the NIH/National Cancer Institute grant R01 CA207110.; The PanGenEU study was funded by: Fondo de Investigaciones Sanitarias (FIS), Instituto de Salud Carlos III, Spain (#PI11/01542, #PI0902102, #PI12/01635, #PI12/00815, #PI15/01573); European Cooperation in Science and Technology – COST Action #BM1204; EUPancreas EU-6FP Integrated Project (#018771-MOLDIAG-PACA), EU-FP7-HEALTH (#259737-CANCERALIA, #256974-EPC-TM-Net).; In addition, other NIH funds contributed to the support of the investigators: P30 CA168525, and the Kansas IDeA Network of Biomedical Research Excellence Bioinformatics Core, supported in part by the National Institute of General Medical Science (NIGMS) Award P20GM103418.
• Keywords: Life Sciences & Biomedicine; Science & Technology; Public, Environmental & Occupational Health; Oncology
• Research Categories: Health Sciences, Epidemiology; Health Sciences, Public Health; Biology, Molecular; Health Sciences, Oncology; Biology, Cell

Abstract

Background: Pancreatic cancer is projected to become the second most common cause of cancer-related death over the next 5 years. Because inflammation is thought to be a common trajectory for disease initiation, we sought to prospectively characterize immune profiles using DNA methylation markers and examine DNA methylation levels previously linked to inflammation biomarkers to evaluate whether these immune markers play a key role in pancreatic cancer. Methods: In a nested case–control study pooling three U.S. prospective cohort studies, DNA methylation was measured in prediagnostic leukocytes of incident pancreatic cancer cases and matched controls using the Illumina MethylationEPIC array. Differentially methylated regions were used to predict immune cell types, and CpGs previously associated with inflammatory biomarkers were selected for the analysis. DNA methylation data from a retrospective case–control study conducted in Spain (PanGenEU) was used for independent replication. Results: Immune cell proportions and ratio of cell proportions were not associated with pancreatic cancer risk in the nested case–control study. Methylation extent of CpGs residing in or near gene MNDA was significantly associated with pancreatic cancer risk in the nested case–control study and replicated in PanGenEU. Methylation level of a promoter CpG of gene PIM-1 was associated with survival in both studies. Conclusions: Using a targeted approach, we identified several CpGs that may play a role in pancreatic carcinogenesis in two large, independent studies with distinct study designs. Impact: These findings could provide insight into critical pathways that may help identify new markers of early disease and survival.