Endogenous mutational mechanisms and metabolic context shape endometrial cancer

Uterine corpus endometrial carcinoma (UCEC) is a common gynecologic malignancy with rising mortality, yet its genome-wide mutational architecture remains incompletely understood. Here we analyze deep whole-genome sequencing data from 440 UCEC tumors from The Cancer Genome Atlas, integrated with transcriptomic and clinical data, to define subtype-specific mutational processes and genomic architectures. We uncover pronounced molecular subtype-specific differences in endogenous mutational mechanisms, retrotransposition activity, structural variation, and chromosomal instability. LINE-1 retrotransposition emerges as a key contributor to genome instability in UCEC, acting as a prominent source of structural variation in copy-number stable tumors and associating with chromothripsis and ecDNA-mediated oncogene amplification in copy-number high tumors. Mutational signature SBS28 contributes significantly to mutations in POLE-deficient tumors and is strongly correlated with SBS10a and SBS10b. Mismatch repair-deficient tumors exhibit a previously unrecognized doublet base substitution signature and a defining imbalance between ID2 and ID1 indel processes, reflecting pervasive DNA template-strand replication slippage and associated with increased tumor immunogenicity. Copy-number low tumors follow a distinct low-mutagenesis evolutionary trajectory characterized by reduced replication stress, low proliferative activity, genomic stability and enrichment of SBS18 associated with oxidative damage. Notably, we identify a consistent inverse association between body mass index and tumor mutational burden in UCEC, suggesting that host metabolic state may influence fundamental cellular processes governing mutation accumulation, promoting tumor development through non-mutagenic mechanisms rather than elevated genomic instability. Together, these findings establish a mutagenesis-centric framework for UCEC that links endogenous mutational mechanisms to tumor architecture and host metabolic context, uncovering previously unrecognized subtype-specific genomic features with important implications for refined risk stratification and therapeutic strategies.