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.

Secreted proteins (SPs) play important roles in diverse important biological processes; however, a comprehensive and high-quality list of human SPs is still lacking. Here we identified 6,943 high-confidence human SPs (3,522 of them are novel) based on 330,427 human proteins derived from databases of UniProt, Ensembl, AceView, and RefSeq. Notably, 6,267 of 6,943 (90.3%) SPs have the supporting evidences from a large amount of mass spectrometry (MS) and RNA-seq data. We found that the SPs were broadly expressed in diverse tissues as well as human body fluid, and a significant portion of them exhibited tissue-specific expression. Moreover, 14 cancer-specific SPs that their expression levels were significantly associated with the patients' survival of eight different tumors were identified, which could be potential prognostic biomarkers. Strikingly, 89.21% of 6,943 SPs (2,927 novel SPs) contain known protein domains. Those novel SPs we mainly enriched with the known domains regarding immunity, such as Immunoglobulin V-set and C1-set domain. Specifically, we constructed a user-friendly and freely accessible database, SPRomeDB (www.unimd.org/SPRomeDB), to catalog those SPs. Our comprehensive SP identification and characterization gain insights into human secretome and provide valuable resource for future researches.