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Genome-Wide DNA Methylation Analysis Reveals Molecular Subtypes of Pancreatic Cancer

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Genome-Wide DNA Methylation Analysis Reveals Molecular Subtypes of Pancreatic Cancer www.impactjournals.com/oncotarget/ Oncotarget, 2017, Vol. 8, (No. 17), pp: 28990-29012 Research Paper Genome-wide DNA methylation analysis reveals molecular subtypes of pancreatic cancer Nitish Kumar Mishra1 and Chittibabu Guda1,2,3,4 1Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, 68198, USA 2Bioinformatics and Systems Biology Core, University of Nebraska Medical Center, Omaha, NE, 68198, USA 3Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA 4Fred and Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA Correspondence to: Chittibabu Guda, email: [email protected] Keywords: TCGA, pancreatic cancer, differential methylation, integrative analysis, molecular subtypes Received: October 20, 2016 Accepted: February 12, 2017 Published: March 07, 2017 Copyright: Mishra et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC-BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Pancreatic cancer (PC) is the fourth leading cause of cancer deaths in the United States with a five-year patient survival rate of only 6%. Early detection and treatment of this disease is hampered due to lack of reliable diagnostic and prognostic markers. Recent studies have shown that dynamic changes in the global DNA methylation and gene expression patterns play key roles in the PC development; hence, provide valuable insights for better understanding the initiation and progression of PC. In the current study, we used DNA methylation, gene expression, copy number, mutational and clinical data from pancreatic patients. We independently investigated the DNA methylation and differential gene expression profiles between normal and tumor samples and correlated methylation levels with gene expression patterns. We observed a total of ~23-thousand differentially methylated CpG sites (Δβ≥0.1) between normal and tumor samples, where majority of the CpG sites are hypermethylated in PC, and this phenomenon is more prominent in the 5’UTRs and promoter regions compared to the gene bodies. Differential methylation is observed in genes associated with the homeobox domain, cell division and differentiation, cytoskeleton, epigenetic regulation and development, pancreatic development and pancreatic signaling and pancreatic cancer core signaling pathways. Correlation analysis suggests that methylation in the promoter region and 5’UTR has mostly negative correlations with gene expression while gene body and 3’UTR associated methylation has positive correlations. Regulatory element analysis suggests that HOX cluster and histone core proteins are upstream regulators of hypomethylation, while SMAD4, STAT4, STAT5B and zinc finger proteins (ZNF) are upstream regulators of hypermethylation. Non-negative matrix factorization (NMF) clustering of differentially methylated sites generated three clusters in PCs suggesting the existence of distinct molecular subtypes. Cluster 1 and cluster 2 showed samples enriched with clinical phenotypes like neoplasm histological grade and pathologic T-stage T3, respectively, while cluster 3 showed the enrichment of samples with neoplasm histological grade G1. To the best of our knowledge, this is the first genome-scale methylome analysis of PC data from TCGA. Our clustering analysis provides a strong basis for future work on the molecular subtyping of epigenetic regulation in pancreatic cancer. www.impactjournals.com/oncotarget 28990 Oncotarget INTRODUCTION analyze genome-wide methylation patterns in PC. This study used simple Spearman’s correlation of differentially Pancreatic cancer (PC) is the fourth leading cause methylated CpGs to integrate DNA methylation and of cancer deaths today in the United States [1] and it is gene expression data at the gene-level, whereas, we are poised to become the second leading cause within a decade using TCGA data with special emphasis on correlating [2] due to the aggressiveness of the disease and the lack methylations patterns of genes (100KB up and downstream of reliable early diagnostic markers. Survival prospects of of transcription start site (TSS)) with gene expressions, many other cancers have improved over the past decade, but which is biologically more relevant. We are also looking only a marginal change was observed in pancreatic cancer at the methylation patterns at the distal enhancer region, survival. Pancreatic cancer patients have a median survival probable upstream regulator and epigenetic-driven gene in of 6 months and a 5-year survival rate of only 6% despite TCGA PC. Most recently Kim et. al. [17] published on the 50 years of research and therapeutic developments [3]. The pan cancer DNA methylation analysis of TCGA data, but lack of specific symptoms at early stages of tumor initiation, this study uses only twenty three imprinted genes. high biological aggressiveness of the tumor and resistance Epigenetic changes such as DNA methylation to cytotoxic drugs, all contribute to the high mortality rate effect gene regulation in normal development. In normal of PC. In nearly 95% of PC patients there is neither an cells, DNA methylation assures proper regulation of associated family history of PC nor of diseases known to be gene expression and stable gene silencing leading to associated with an increased risk of PC [4]. This points out to physiological homeostasis. Epigenetic signatures are the fact that the etiology of PC is more sporadic than genetic, acquired by cells during cancer tumorogenesis [18], suggesting that epigenetic alterations may play a key role in which in turn allows them to overcome physiological the transcriptional regulation of genes in pancreatic cancer. homeostasis. These properties confer cells with continuous Epigenetic alteration of gene expression can be proliferation potential, self-sufficiency in growth and achieved by DNA methylation, which is known to be apoptotic signals and ability to evade the immune system deregulated in pancreatic cancer resulting in altered gene [19]. Transcriptional silencing or enhancement of critical expression [5, 6], genome structure reorganization, tumor growth regulators through promoter hypermethylation or grade, tumor stage and survival time of patients [3]. The hypomethylation, respectively, also plays a major role in Cancer Genome Atlas (TCGA) [7, 8] and International cancer. Hedgehog and notch signaling pathways are very Cancer Genome Consortium (ICGC) [9] have generated important for proper development of pancreas. Reactivation methylome data for thousands of tumor samples spanning of both of these pathways is common in pancreatic cancer across ~25 cancer types including pancreatic cancer. The [20, 21]. Recent work by Thompson et. al. [3] also suggests large number of available TCGA tumor datasets provides that differential methylation of pancreas development the opportunity to study the global methylation and gene related genes including homeobox-containing genes are expression patterns of PCs with increased statistical power, important for PC development and survival of PC patients. which would not have been possible otherwise. Several Yang et. al. [13] used TCGA data for ten major cancer types DNA methylation pattern analyses were previously reported and observed that methylation and expression patterns of for many cancer types using TCGA data [10–13]; but to epigenetic enzymes can play a major role in many cancers, our knowledge no such report exists for genome scale but this study did not include data from PC patients. methylation pattern analysis of PCs using TCGA datasets. Given the increasing evidence on the role of Earlier studies on PC methylation analysis have epigenetics in cancer, we hypothesize that epigenetic used limited patient samples or CpG sites. Sato et. al. [14] landscape of PC tumors would be distinct compared analyzed genome-scale DNA methylation patterns in PC, to those of the normal tissues and that these epigenetic but the limitation of this study is that they used methylation- alterations can be correlated with the gene expression site-specific polymerase chain reaction for only eight genes. patterns in PCs. It has been shown that DNA methylation Later, Tan et. al. [15] studied the methylation patterns of PC and gene expression of homeobox-containing genes, using data from thirty xenografts, seven adjacent normal pancreas development genes and epigenetic regulatory tissues and fourteen human PC cell lines. This study used genes play a vital role in PC [22]. In the current study, the Illumina GoldenGate Methylation Cancer Panel, which we carried out detailed analysis of the global differential contains 1,536 CpG sites distributed across only 807 genes methylation patterns in individual chromosomes, with low genome coverage. Recently, Thompson et. al. homeobox containing gene family and genes involved in [3] used Illumina Hiseq 2000 methylation data from 16 epigenetic regulation, and clustered the patient population samples (11 tumor, 2 normal and 3 chronic pancreatitis based on these patterns. We correlated the clustered groups sample) to analyze the role of DNA methylation in the with somatic mutation loads and copy number variations survival of PC patients. However, this is a focused study observed in important oncogenes and tumor suppressor on correlating DNA methylation with patient’s survival genes. We
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