Multicancer analyses of short tandem repeat variations reveal shared gene regulatory mechanisms.

Short tandem repeats (STRs) have been reported to influence gene expression across various human tissues. While STR variations are enriched in colorectal, stomach, and endometrial cancers, particularly in microsatellite instable tumors, their functional effects and regulatory mechanisms on gene expression remain poorly understood across these cancer types. Here, we leverage whole-exome sequencing and gene expression data to identify STRs for which repeat lengths are associated with the expression of nearby genes (eSTRs) in colorectal, stomach, and endometrial tumors. While most eSTRs are cancer-specific, shared eSTRs across multiple cancers exhibit consistent effects on gene expression. Notably, coding-region eSTRs identified in all three cancer types show positive correlations with nearby gene expression. We further validate the functional effects of eSTRs by demonstrating associations between somatic eSTR mutations and gene expression changes during the transition from normal to tumor tissues, suggesting their potential roles in tumorigenesis. Combined with DNA methylation data, we perform the first quantitative analysis of the interplay between STR variations and DNA methylation in tumors. We identify eSTRs where repeat lengths are associated with methylation levels of nearby CpG sites (meSTRs) and show that >70% of eSTRs are significantly linked to local DNA methylation. Importantly, the effects of meSTRs on DNA methylation remain consistent across cancer types. Overall, our findings enhance the understanding of how functional STR variations influence gene expression and DNA methylation. Our study highlights shared regulatory mechanisms of STRs across multiple cancers, offering a foundation for future research into their broader implications in tumor biology.