Exploration of a Novel Biomarker in Endometrial Carcinoma

Background: The adenomatous polyposis coli (APC) gene, located on chromosome 5q21, is the chromatin-remodeling related gene and a typical tumor suppressor. As reported, patients with high expression of programmed death-ligand 1 (PD-L1) or a high level of tumor mutational burden (TMB) may benefit from immunotherapy in endometrial cancer. The objective of this study was to demonstrated that APC as a new target for the diagnosis and treatment of endometrial cancer, by analyzing the correlation of APC with PD-L1 expression or TMB. Methods: We performed an integrative analysis of a commercial panel including 520 cancer-related genes on 99 tumors from an endometrial cancer cohort in China and DNA-seq data from The Cancer Genome Atlas (TCGA) to identify new gene mutations as endometrial cancer immunotherapy markers. To determine the effect of gene mutations on endometrial cancer, we explored the correlation between gene mutations and tumor immune microenvironment, and explored the immune microenvironment in endometrial cancer, including TMB, PD-L1 expression and lymphocytic infiltration. Results: We found that the significant mutant genes were related to the chromatin state and generated a discovery set including 12 mutated genes that significantly correlated with PD-L1 expression and TMB. We identified the APC gene, with 19% (18/99) mutation rate, as a new marker for immunotherapy. Further analysis revealed that tumors with the APC mutation had a high TMB, increased expression of PD-L1 and increased lymphocytic infiltration (all P <0.02). By assessing the relationship between immunotherapy biomarkers and APC, we verified that APC have inactive mutation in endometrial cancer, which may affect the immune response, including PD-L1 expression, microsatellite instability and lymphocytic infiltrate. Using TCGA data, we found that patients with the APC mutation had longer overall survival. Conclusion: Our study demonstrates that APC could play an important role in enhancing the response to endometrial cancer treatment, particularly immunotherapy.