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BACKGROUND@#Lung cancer still has the highest incidence rate and mortality rate nowadays. In recent years, with the emergence of new drugs and the optimization of treatment mode, especially the clinical application of immunotherapy, the prognosis of lung cancer patients has been improved. However, the benefits of immunotherapy are still limited. Therefore, it is necessary to find new biomarkers to predict the prognosis of lung adenocarcinoma patients and explore its impact on the immune microenvironment.@*METHODS@#The Cancer Genome Atlas (TCGA) database was used to analyze the gene sequencing and clinical data of patients with lung adenocarcinoma. The distribution of RASGRP2 in lung adenocarcinoma was determined by using the human protein mapping database. The Kaplan-Meier plotter database was used to explore the relationship between the expression of RASGRP2 and the prognosis of patients with lung adenocarcinoma. KEGG and GO gene enrichment analysis was performed in patients with high and low expression of RASGRP2. TCGA database was used to analyze the co-expression genes of RASGRP2 and TIMER database was used to calculate the immune related lymphoid infiltration of RASGRP2 and its coexpression genes. The relationship between RASGRP2 expression and immune checkpoint expression was analyzed by using TIMER 2.0 database.@*RESULTS@#We found that RASGRP2 was low expressed in lung adenocarcinoma, and its expression level was related to the prognosis of patients. The high expression of RASGRP2 was involved in the process of hematopoietic cell formation and cell adhesion, and RASGRP2 played an important role in the process of T cell activation. Through TCGA database analysis, ZAP70, TBC1D10C, RASAL3, FGD2, CD37 and ACAP1 were significantly correlated with RASGRP2. The high expression of these genes leaded to the increase of the proportion of CD8+ T cells, memory CD4+ T cells, and the decrease of the proportion of neutrophils and Treg cells. Finally, we found that the expression of RASGRP2 was significantly correlated with the expression of CD274, CTLA4, LAG3 and TIGIT.@*CONCLUSIONS@#RASGRP2 was abnormally expressed in lung adenocarcinoma and correlated with the infiltration level of immune related cells, which might influence the efficacy of immunotherapy.
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Objective@#To review the clinical characteristics of a pedigree with inherited hemorrhagic disease to explore its molecular pathogenesis.@*Methods@#The clinical data of the pedigree with inherited hemorrhagic disease were collected. After extracting DNA, next generation sequencing was utilized to detect the potential gene mutation. The changes of RASGRP2 transcript of this proband and his parents were detected using RT-PCR to compare with normal control.@*Results@#The phenotype of the proband in this pedigree with inherited platelet dysfunction and bleeding disorder was similar to variant Glanzmann’s thrombasthenia, the maximum aggregations of platelet in response to the physiological agonists including ADP, epinephrine and arachidonic acid were significantly lower, leading to severe spontaneous mucosal bleeding. Integrin αIIbβ3 gene mutation was not detected, but another gene mutation RASGRP2 IVS3-1 stood out. The mutation was homozygous in the proband and heterozygosis in both of his parents. Two transcript types were detected in the proband, without transcripts coding functional RASGRP2 protein, however, his parents had functional transcripts and abnormal transcripts, with the normal transcripts in the majority.@*Conclusions@#The RASGRP2 IVS3-1 gene mutation was responsible for the inherited hemorrhagic disease. The RASGRP2 IVS3-1 gene mutation led to abnormal alternative splicing, without formation of functional RASGRP2 protein. The RASGRP2 protein is at the nexus of calcium-dependent platelet activation and hemostasis after damage of blood vessels. Spontaneous mucosal bleeding was a result of the lack of the functional RASGRP2 protein. This was the first report of RASGRP2 gene mutation resulting in bleeding disorder in China, and also the first report of the mutation type of RASGRP2 IVS3-1.
RESUMEN
Objective: To review the clinical characteristics of a pedigree with inherited hemorrhagic disease to explore its molecular pathogenesis. Methods: The clinical data of the pedigree with inherited hemorrhagic disease were collected. After extracting DNA, next generation sequencing was utilized to detect the potential gene mutation. The changes of RASGRP2 transcript of this proband and his parents were detected using RT-PCR to compare with normal control. Results: The phenotype of the proband in this pedigree with inherited platelet dysfunction and bleeding disorder was similar to variant Glanzmann's thrombasthenia, the maximum aggregations of platelet in response to the physiological agonists including ADP, epinephrine and arachidonic acid were significantly lower, leading to severe spontaneous mucosal bleeding. Integrin αIIbβ3 gene mutation was not detected, but another gene mutation RASGRP2 IVS3-1 stood out. The mutation was homozygous in the proband and heterozygosis in both of his parents. Two transcript types were detected in the proband, without transcripts coding functional RASGRP2 protein, however, his parents had functional transcripts and abnormal transcripts, with the normal transcripts in the majority. Conclusions: The RASGRP2 IVS3-1 gene mutation was responsible for the inherited hemorrhagic disease. The RASGRP2 IVS3-1 gene mutation led to abnormal alternative splicing, without formation of functional RASGRP2 protein. The RASGRP2 protein is at the nexus of calcium-dependent platelet activation and hemostasis after damage of blood vessels. Spontaneous mucosal bleeding was a result of the lack of the functional RASGRP2 protein. This was the first report of RASGRP2 gene mutation resulting in bleeding disorder in China, and also the first report of the mutation type of RASGRP2 IVS3-1.