Co-occurrence and Mutual Exclusivity Analysis of DNA Methylation Reveals Distinct Subtypes in Multiple Cancers

Abstract

Co-occurrence and mutual exclusivity (COME) of DNA methylation refer to two or more genes that tend to be positively or negatively correlated in DNA methylation among different samples. Although COME of gene mutations in pan-cancer have been well explored, little is known about the COME of DNA methylation in pan-cancer. Here, we systematically explored the COME of DNA methylation profile in diverse human cancer. A total of 5,128,332 COME events were identified in 14 main cancers types in The Cancer Genome Atlas (TCGA). We also identified functional epigenetic modules of the zinc finger gene family in six cancer types by integrating the gene expression and DNA methylation data and the frequently occurred COME network. Interestingly, most of the genes in those functional epigenetic modules are epigenetically repressed. Strikingly, those frequently occurred COME events could be used to classify the patients into several subtypes with significant different clinical outcomes in six cancers as well as pan-cancer (p-value ≤ = 0.05). Moreover, we observed significant associations between different COME subtypes and clinical features (e.g., age, gender, histological type, neoplasm histologic grade, and pathologic stage) in distinct cancers. Taken together, we identified millions of COME events of DNA methylation in pan-cancer and detected functional epigenetic COME events that could separate tumor patients into different subtypes, which may benefit the diagnosis and prognosis of pan-cancer.

Genome-wide methylation patterns predict clinical benefit of immunotherapy in lung cancer

“…Previous studies have revealed mutually exclusive patterns of genomic alterations across cancer patients, including mutations in driver genes [ 26 ]. Genes exhibiting mutually exclusive alternation pattern are generally involved in a common biological pathway due to their functional redundancy [ 27 , 28 ]. Knowledge about these patterns can provide important insight into novel cancerous network and potential therapeutic targets [ 29 ].…”

Methylation silencing CDH23 is a poor prognostic marker in diffuse large B-cell lymphoma

“…DNMIVD ( http://www.unimd.org/dnmivd/ ) is a database that allows researchers to build molecular models for diagnosis and prognosis of cancer based on methylation of DNA, and visualizes the methylation profile of gene promoters and CpGs from various aspects [ 52 – 54 ]. We analyzed the expression level and methylation value of CDH23 in breast invasive carcinoma (BRCA) and normal tissues, and further calculated the Pearson correlation between methylation of CDH23 promoter and Fragments Per Kilobase of exon model per Million mapped fragments (FPKM) in BRCA.…”

The Prognostic Value and Immunological Role of STEAP1 in Pan-Cancer: A Result of Data-Based Analysis

“…The methylation difference of STEAP1 between normal and tumor samples was evaluated. DNA methylation interactive visualization database (DNMIVD, http://119.3.41.228/ dnmivd/index/) was used to investigate the methylation of STEAP1 regarding the correlation between STEAP1 expression level in Fragments Per Kilobase Million (FPKM) form and the methylation level of its promoter [19][20][21]. The mutation exploration was carried out by cBioPortal (https://www.cbioportal.org/), an open-access resource for interactive analysis of all-round cancer genomics datasets.…”