Date of Award

January 2021

Document Type


Degree Name

Medical Doctor (MD)



First Advisor

Gary Altwerger


DNA mismatch repair deficiency is the distinguishing molecular feature of a significant portion of endometrial cancers. Tumors with mismatch repair deficiency exhibit significantly higher mutational burden, and have been identified as candidates for immune checkpoint blockade therapy. However, the relationship between mismatch repair deficiency and clinical outcomes in endometrial cancer has not been clearly defined. Recently, using genome sequencing-based methods, pan-cancer analysis has characterized mutational signatures associated with mismatch repair deficiency. We sought to understand the relationship between defective mismatch repair associated mutational signatures and alterations in key mismatch repair genes in endometrial cancer. We also studied how defective mismatch repair associated mutational signatures influence the immune landscape in endometrial cancer. Using whole-exome sequencing MC3 data from primary endometrioid, serous and mixed endometrioid/serous carcinomas in The Cancer Genome Atlas (TCGA), we analyzed the defective mismatch repair (MMRd) associated mutational signatures for 507 samples using deconstructSigs, and correlated MMRd mutational signatures with clinical and molecular features. TCGA samples were divided into High MMRd mutational signature (n = 192) and Low MMRd mutational signature (n = 315) groups. Our analysis revealed that patients in the High MMRd group had longer progression-free survival (p = 0.0457, log-rank). A significantly higher percentage of patients (47/192, 24.5%) in the High MMRd group had somatic putative driver mutations in at least 1 of the mismatch repair genes compared with patients in the Low MMRd group (37/315, 11.8%, p = 0.0002). Furthermore, we found that MMRd mutational signature positively correlated with MLH1 promoter methylation (r = 0.60, p < 0.0001). Additionally, 15% (54/359) of tumors from the non-MSI subtypes and without significant MMR deficiency were also categorized in the High MMRd group. Our analysis of the inferred composition of tumor-infiltrating immune cells using data derived from CIBERSORT revealed that tumors in the High MMRd group had significantly higher fraction of CD8+ T cells ( p < 0.0001), higher fraction of T follicular helper cells (p < 0.0001) and lower fraction of M2 macrophages (p < 0.001). Tumors in the High MMRd group also displayed higher expression levels of immune checkpoint genes. These findings indicate a more active immune microenvironment in tumors in the High MMRd group. Overall, our data suggest that MMRd mutational signature may be used in concert with traditional methods to identify patients with a defective mismatch repair phenotype, and to potentially predict response to immune checkpoint inhibitor therapy in endometrial cancer.


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