Integrated analysis of LRP2 mutation to immunotherapy efficacy in pan-cancer cohort

Abstract

Purpose Immunotherapy has emerged as a novel therapy, while many patients are refractory. Although, several biomarkers have been identified as predictive biomarkers for immunotherapy, such as tumor specific genes, PD-1/PD-L1, tumor mutation burn (TMB), and microsatellite instability (MSI), results remain unsatisfactory.Methods We investigated the characteristics of low-density lipoprotein receptor-related protein 2 (LRP2) mutation in the cancer genome atlas (TCGA) and explored the potential association of LRP2 mutation with immunotherapy. Characteristic of LRP2 mutation in 33 cancer types was analyzed using large-scale public data. The association of LRP2 mutation with immune cell infiltration and immunotherapy efficacy was evaluated. Finally, a LPR2 mutation signature (LMS) was developed and validated by TCGA-UCEC and pan-cancer cohorts. Furthermore, we demonstrated the predictive power of LMS score in independent immunotherapy cohorts by performing a meta-analysis.Results Our results revealed that patients with LRP2 mutant had higher TMB and MSI compared with patients without LRP2 mutation. Meanwhile, LRP2 mutation was associated with higher infiltration level of immune cells and higher expression of immune-related genes and signaling pathways. Patients with LRP2 mutation presented long overall survival (OS) after immunotherapy. In endothelial cancer (EC), patients with LRP2 mutation belonged to the POLE and MSI-H type of EC molecular types, with a better prognosis. Finally, we developed a LRP2 mutation signature (LMS), that was significantly associated with prognosis in patients receiving immunotherapy.Conclusion These results indicated that LRP2 mutation can serve as a biomarker for the personalization of cancer immunotherapy. Importantly, LMS is a potential predictor of patients prognosis after immunotherapy.