Molecular evolution of driver mutations in cancer with microsatellite instability and their impact on tumor...

Cancer development is driven by genetic alterations, particularly cancer driver mutations (CDMs), which are associated with aggressive phenotypes and shorter survival. In contrast, higher mutation loads caused by microsatellite instability (MSI) or mismatch repair deficiency (MMRd) can induce anti-cancer immunity, leading to tumor shrinkage and improved responses to immune checkpoint inhibitor (ICI) therapies. However, understanding how CDMs and MSI/MMRd influence cancer evolution remains limited. We opted uterine corpus endometrial carcinoma (UCEC) as a model in this study due to its MSI-high/MMRd characteristics. Somatic mutation screening revealed that UCEC has a significantly higher mutation rate in cancer driver genes compared to ovarian cancer (OVCA) and cervical squamous cell carcinoma (CSCC), despite these cancers arising from histologically connected organs in the reproductive tract. Interestingly, these CDMs did not necessarily drive tumor progression. Using a cutoff of 7.0 (mutations/Mb) for tumor mutation burden (TMB), we classified UCEC patients into two groups with distinct clinical features, genetic profiles, and drug sensitivities. Among the known CDMs, TP53 mutations and their functional networks emerged as key drivers in UCEC progression, while mutations in CTNNB1, PTEN, and ARID1A may enhance anti-tumor immunity, correlating with longer overall survivals. Drug screening using GDSC and CTRPv2 databases suggested that GSK-3 inhibitor IX may be effective for treating aggressive UCEC patients with a non-MSI phenotype. Curcumin showed efficacy for UCEC patients with MSI, especially with ICI therapy. Our study highlights the importance of immune regulation and tolerance over CDMs in cancer development, particularly in those with an MSI-high/MMRd phenotype. We propose that TMB could serve as a valuable screening method alongside molecular and histopathological classifications to guide treatment strategies for UCEC patients.