Oncotarget

Research Papers:

Genome-wide DNA methylation analysis reveals molecular subtypes of pancreatic cancer

Nitish Kumar Mishra and Chittibabu Guda _

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Oncotarget. 2017; 8:28990-29012. https://doi.org/10.18632/oncotarget.15993

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Abstract

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: babu.guda@unmc.edu

Keywords: TCGA, pancreatic cancer, differential methylation, integrative analysis, molecular subtypes

Received: October 20, 2016    Accepted: February 12, 2017    Published: March 07, 2017

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.


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