Integrated genomic and transcriptomic profiling across the clinical spectrum of Lynch syndrome-associated endometrial disease

We investigated the molecular processes underlying the clinical spectrum of Lynch syndrome (LS)-associated endometrial disease using integrated genomic and transcriptomic profiling of endometrial tissues. Whole-transcriptome sequencing revealed distinct patterns of immune remodeling across clinically defined disease states (unaffected carrier, premalignant, and malignant states), characterized by increasing infiltration of T cells, particularly CD8+ subsets and B cells. Non-negative matrix factorization of transcriptomic profiles identified two cancer-associated features and one feature enriched in normal endometrium, with validation in external datasets. A dominant cancer-associated feature was characterized by immune activation, effector T-cells, and exhaustion-associated CD8+ T-cell transcriptional signatures, consistent with an immune-active microenvironment. Whole-exome sequencing identified oncogenic mutations and mismatch repair deficiency –associated mutational signatures in premalignant lesions, suggesting that these alterations are already detectable in premalignant lesions within the LS disease spectrum. Together, these findings suggest distinct immune and genomic alterations across the clinical spectrum of LS-associated endometrial disease, providing molecular insights that may inform future biomarker development and prevention-oriented studies in high-risk individuals.