Abstract
Background: Understanding the role of repetitive elements (REs) in cancer development is crucial for identifying novel biomarkers and therapeutic targets. Methods: This study investigated the locus-specific dysregulation of REs, including the differential expression and methylation of REs, across 12 TCGA cancer types stratified by their genomic context (i.e., genic and intergenic REs). Results: We found uniquely dysregulated genic REs co-regulated with their corresponding transcripts and associated with distinct biological functions in different cancer types. Uniquely dysregulated intergenic REs were identified in each cancer type and used to cluster different sample types. Recurrently dysregulated REs were identified in several cancer types, with genes associated with up-regulated genic REs involved in cell cycle processes and those associated with down-regulated REs involved in the extracellular matrix. Interestingly, four out of five REs consistently down-regulated in all 12 cancer types were located in the intronic region of the TMEM252, a recently discovered tumor suppressor gene. TMEM252 expression was also down-regulated in 10 of 12 cancer types, suggesting its potential importance across a wide range of cancer types. With the corresponding DNA methylation array data, we found a higher prevalence of hypo-methylated REs in most cancer types (10 out of 12). Despite the slight overlaps between differentially expressed REs and differentially methylated REs, we showed that the methylation of locus-specific REs negatively correlates with their expression in some of these 12 cancer types. Conclusions: Our findings highlight the cancer-specific and recurrent deregulation of REs, their functional associations, and the potential role of TMEM252 as a pan-cancer tumor suppressor, providing new insights into biomarker discovery and therapeutic development.