Esophageal Cancer Epigenomics and Integrome Analysis of Genome-Wide Methylation and Expression in High Risk Northeast Indian Population

Abstract

Esophageal cancer is a major global health burden with a strong host-environment interaction component and epigenomics underpinnings that remain to be elucidated further. Certain populations such as the Northeast Indians suffer at a disproportionately higher rate from this devastating disease. Promoter methylation is correlated with transcriptional silencing of various genes in esophageal cancer. Very few studies on genome-wide methylation for esophageal cancer exist and yet, no one has carried out an integromics analysis of methylation and gene expression. In the present study, genome-wide methylation was measured in samples collected from the Northeast Indian population by Infinium 450k array, and integration of the methylation data was performed. To prepare a network of genes displaying enriched pathways, together with the list of genes exhibiting promoter hypermethylation or hypomethylation with inversely correlated expression, we performed an integrome analysis. We identified 23 Integrome network enriched genes with relevance to tumor progression and associated with the processes involved in metastasis such as cell adhesion, integrin signaling, cytoskeleton, and extracellular matrix organizations. These included four genes (PTK2, RND1, RND3, and UBL3) with promoter hypermethylation and downregulation, and 19 genes (SEMG2, CD97, CTNND2, CADM3, OMD, NEFM, FBN2, CTNNB1, DLX6, UGT2B4, CCDC80, PZP, SERPINA4, TNFSF13B, NPC1, COL1A1, TAC3, BMP8A, and IL22RA2) with promoter hypomethylation and upregulation. A Methylation Efficiency Index was further calculated for these genes; the top five gene with the highest index were COL1A1, TAC3, SERPINA4, TNFSF13B, and IL22RA2. In conclusion, we recommend that the circulatory proteins IL22RA2, TNFSF13B, SERPINA4, and TAC3 in serum of patients and disease-free healthy controls can be examined in the future as putative noninvasive biomarkers.

Adhesion GPCRs in Tumorigenesis

“…In a study of 37 pancreatic cancer patients, CD97 correlates with aggressiveness and was associated with prognosis [54]. In esophageal cancer CD97 is among the 19 genes with promoter hypomethylation and upregulation [140]. …”

Differences in cancer gene copy number alterations between Epstein‐Barr virus‐positive and Epstein‐Barr virus‐negative nasopharyngeal carcinoma

“…Thus, MCCC1 may be a predictive marker for survival in NPC in general. [32][33][34] Its protein form has been described as being increasingly phosphorylated in EBV-infected cells, 35 and shows recurrent rearrangements in NPC tissue. As previously mentioned, the EBV-negative and EBVpositive NPC tumors showed similarities in cancer gene CNA suggesting that there might be a common oncogenic pathway but these tumors probably ultimately diverge and develop their own different molecular routes as there were also important CNA differences between the EBV-negative and EBV-positive NPCs.…”

“…31 PTK2, which was also found to be gained/amplified in EBV-positive NPC, as mentioned earlier, is a transcriptional factor involved in apoptosis, cell proliferation, and resistance to cell death. [32][33][34] Its protein form has been described as being increasingly phosphorylated in EBV-infected cells, 35 and shows recurrent rearrangements in NPC tissue. 36 Interesting in our cohort is the finding that PTK2 correlated with worse DFS in EBVinfected NPC, and as PTK2 is a therapeutic target in breast cancer, 37,38 it might also be a target in EBV-positive NPC.…”

Multi-omics and male infertility status integration and future prospects

“…A summary of the different 'omics' techniques is illustrated in figure 1 (Figure 1). In other pathological manifestations, such as cancer, there are reports available that discover the new horizons by cross omics data integration, rather than with a single set of data (102,103). The study highlights the integration of genome wide methylation and mRNA expression in esophageal cancer thereby exploring the complex interactions involved (102).…”