Factors in Genetic Alterations in DNA Repair Pathways and Their Effects on Endometrial Cancer

Introduction: Endometrial cancer is the most common gynecological neoplasm, with its origins closely linked to genetic alterations. This study highlights mutations in genes involved in DNA repair, especially the mismatch repair system and the BRCA1/2 genes, as central elements in the development of the disease, its molecular profile, and response to treatments. Understanding these genetic impacts is crucial to improving diagnostic methods and driving the development of personalized therapeutic approaches. Methodology: A literature review was conducted, searching for articles in the PubMed and Scopus databases. Inclusion criteria included molecular, clinical, and epidemiological studies that established a correlation between mutations in DNA repair genes and endometrial cancer, published in the last ten years. The selected studies were analyzed to gather information on the prevalence of mutations in the mismatch repair system and BRCA1/2 genes, the frequency of microsatellite instability, the clinical and molecular profiles of the tumors, and the impact of these alterations on the response to therapies, especially immunotherapy. Results: The results of the review indicate that mismatch repair deficiency, caused by germline mutations or epigenetic methylation, represents a relevant molecular event in approximately 20 to 30% of endometrial cancer cases. This deficiency is associated with microsatellite instability and a hypermutated phenotype, characterized by a high mutational burden. This condition makes the tumor more immunogenic, favoring a positive response to immunotherapy with immune checkpoint inhibitors. Furthermore, germline mutations in the MMR genes are linked to Lynch Syndrome, which significantly increases the risk of developing endometrial cancer in young women. Mutations in the BRCA1/2 genes have also been identified, especially in the more aggressive serous subtype, suggesting a role in homologous recombination deficiency and tumor progression. Conclusion: Genetic alterations in genes responsible for DNA repair play a key role in the molecular biology of endometrial cancer. They not only determine specific molecular subtypes of the disease but also serve as valuable indicators for diagnosis, prognostic assessment, and patient selection for targeted therapies.