Effect Of The CACNA1C Mutation On Immunotherapy Prognosis And The Expression Of CACNA1C In Relation To Tumor Metastasis In Melanoma

Background and PurposeMalignant melanoma is a highly malignant tumour.Immunotherapy is one of the main treatments for advanced melanoma.However,existing biomarkers for melanoma immunotherapy have limitations,and studies have found that more than half of melanoma patients progress to metastasis after immunotherapy,with metastasis being the most important predictor of prognosis.There is therefore an urgent need to find novel and reliable biomarkers to predict the efficacy of melanoma immunotherapy and tumor metastasis.The calcium voltage-gated channel A1C(CACNA1C)gene plays a regulatory role in the development of many tumors,but its mutation and expression in malignant melanoma have not been investigated.In this study,we systematically analyzed the relationship between the mutation status of CACNA1C gene and the prognosis of malignant melanoma patients receiving immunotherapy,and secondly,we attempted to elucidate whether the expression level of CACNA1C gene could predict tumor angiogenesis and metastasis progression in malignant melanoma.Methods1.In the section on the association between CACNA1C mutation status and prognosis of immunotherapy in malignant melanoma,we collected the immunotherapy cohort and divided the patients into CACNA1C mutation group(CACNA1C-MT)and CACNA1C wild group(CACNA1C-WT)according to CACNA1C mutation or not,using one-way Cox regression model analysis and survival curve analysis to predict the relationship between CACNA1C mutation status and prognosis of immunotherapy for malignant melanoma.Meanwhile,immunogenicity,tumor microenvironment cellular infiltration,immune-related genes and pathway enrichment were analysed under different CACNA1C mutation status using the malignant melanoma cohort from the(The Cancer Genome Atlas)TCGA database and a local cohort from Zhujiang Hospital of Southern Medical University.2.In the correlation section between CACNA1C expression levels and malignant melanoma metastasis,we compared the differences in CACNA1C gene expression between malignant melanoma metastatic tissues and tumor primary tissues using the TIMER 2.0(Tumor Immune Estimation Resource)database,and the differences in endothelial cell infiltration between different CACNA1C expression levels,which were finally validated by immunohistochemical experiments.Results1.The CACNA1C mutation was associated with an improved prognosis for immunotherapy.patients in the CACNA1C mutation group(CACNA1C-MT)had higher immunogenicity and lower endothelial cell infiltration.Pathway enrichment analysis showed that antitumor immune response pathways(Response to tumor necrosis factor,Interferon alpha/beta signaling)were significantly enriched in the CACNA1C mutant group(CACNA1C-MT)and pro-tumor pathways(Blood vessel endothelial cell proliferation pathway,Regulation of vascular endothelial growth factor receptor pathway)were significantly downregulated in the CACNA1C mutant group(CACNA1C-MT).2.In metastatic melanoma,CACNA1C expression levels were markedly increased,and there was a positive correlation between CACNA1C expression levels and the degree of endothelial cell infiltration.The outcomes of the immunohistochemistry tests agreed with the findings of the bioinformatics analysis.Conclusion1.CACNA1C mutations are associated with improved immunotherapeutic efficacy in patients with malignant melanoma,and CACNA 1C mutation status is expected to be a novel biomarker for predicting the efficacy of immunotherapy in patients with malignant melanoma.2.CACNA1C expression was significantly higher in metastatic tissues of malignant melanoma than in the primary tumor.High CACNA1C expression levels may contribute to the angiogenesis and metastatic progression of malignant melanoma by promoting endothelial cell production,suggesting that high CACNA1C expression levels may be used as a potential biomarker to predict malignant melanoma metastasis.