Abstract B22: Integrative analysis of DNA methylation and gene expression data reveals complex regulation of gastric cancer
Authors: Yoo Seungyeul , Leung Suet Yi , Zhu Jun 
Published: May 2016

Gastric cancer is a heterogeneous disease where diverse genetic and epigenetic alternations can accumulate in different molecular and histological subtypes. We applied our recently developed causality test between genome-wide DNA methylation and gene expression profiles to three independent cohorts of gastric tumors (97 in Hong Kong University (HKU), 159 in University of Singapore (Singapore) and 365 samples in TCGA stomach adenocarcinoma (TCGA) ). We focused on methylation variations within CpG islands in promoter regions, where global hypermethylation was observed, and identified 37, 62, and 537 key regulators in HKU, Singapore, and TCGA dataset respectively. There were 5 common key regulators (ADHFE1, CDO1, COX7A1, FSTL1, and TCF21) whose methylation variations had high impact on mRNA level changes of large number of downstream genes in all three dataset where different cohorts were profiled using different platforms. When we compared two dataset, there were 5 common key regulators in HKU and Singapore dataset (Fisher's exact test (FET) p-value = 2.9×e-07), 27 common key regulators in HKU and TCGA dataset (FET p-value = 6.8×e-35), and 30 common key regulators in Singapore and TCGA dataset (FET p-value = 1.0×e-29). By combining these, 52 genes were identified as key regulators within at least two dataset. Several of the key regulators were known for the association between their epigenetic disruption and the disease (for example, BNIP3, CDO1, TCF21, ZSCAN18, and so on) while other genes have not implicated in the gastric cancer previously. More interestingly, the downstream genes of these key regulators were significantly overlapped and the directions of correlation with methylation levels were almost same within the three dataset. Further clustering key regulators based on their downstream genes overlaps revealed that there were two distinct groups of downstream genes commonly regulated by these key regulators and the expression of these two groups were anti-correlated. One group was enriched for cell cycle related genes and the other group was enriched for genes involved in immune responses. This result indicates that cell cycle and immune response functions were inversely regulated by methylation variations of the same set of genes. It is worth to note that methylation patterns of some key regulators were subtype dependent and the subtype specific methylation patterns were only observed in tumor samples, but not in adjacent normal tissues. Based on integrative analysis of genome-wide DNA methylation and gene expression profiles within three independent gastric cancer dataset, we identified a set of key regulators whose methylation changes might play a ‘causal' role in the transcriptional regulation associated with the gastric cancer. Further experiments are needed to validate and dissect these putative candidate genes' roles in tumorigenesis and progression of this complex and heterogeneous disease.

Citation Format: Seungyeul Yoo, Suet Yi Leung, Jun Zhu. Integrative analysis of DNA methylation and gene expression data reveals complex regulation of gastric cancer. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr B22.