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

Abstract

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. The aim of this study is to evaluate the value of LRP2 mutations in predicating cancer immunotherapy. 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 mutations with immunotherapy. Characteristics of LRP2 mutations in 33 cancer types were analyzed using large-scale public data. The association of LRP2 mutations 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 mutations. LRP2 mutations were associated with high levels of immune cells infiltration, immune-related genes expression and enrichment of immune related signaling pathways. Importantly, LRP2-mutated patients had a long overall survival (OS) after immunotherapy. In the endometrial cancer (EC) cohort, we found that patients with LRP2 mutations belonged to the POLE and MSI-H type and had a better prognosis. Finally, we developed a LRP2 mutations signature (LMS), that was significantly associated with prognosis in patients receiving immunotherapy. Conclusion These results indicated that LRP2 mutations can serve as a biomarker for personalized tumor immunotherapy. Importantly, LMS is a potential predictor of patients’ prognosis after immunotherapy.