| Background and objectiveGastric cancer is a common malignant tumor with a poor prognosis and it is the second leading cause of cancer-related deaths in China,which cause a severe health burden.In recent years,the development of traditional treatments for gastric cancer such as chemotherapy,targeted therapy and radiation therapy has entered a bottleneck period.While immunotherapy,especially immune checkpoint inhibitors(ICIs)therapy,has gradually been adopted in the treatment of other cancer and it has emerged to set off a research boom.At present,there are a large number of clinical studies related to the treatment of ICIs in gastric cancer.But unlike the exciting therapeutic results in other cancers,ICIs therapy in gastric cancer do not have satisfactory results.Therefore,it is particularly important to look for biomarkers related to ICIs therapy and to screen the populations who can benefit from the treatment.TP53 and ARID1 A are high-frequency mutant genes in gastric cancer.Current research indicates that TP53 and ARID1 A gene mutations are related to one or several indicators of tumor mutational burden,microsatellite instability,tumor infiltration lymphocytes,and PD-L1 expression,which has been proven to be effective in predicting the efficacy of ICIs therapy in multiple studies.So does the co-mutation of TP53 and ARID1 A have potential predictive value to the ICIs therapy in gastric cancer?MethodsWe performed systematically analysis on multiple data types including genomic,m RNA and protein expression from public database such as TCGA,ICGC,and c Bio Portal.Next-generation sequencing and MSIsensor were used to detect gene mutations and MSI status of samples in our center.Types and content of TILs in the tumor microenvironment were assessed by ESTIMATE and CIBERSORT.The predictive value of gene mutations on the efficacy of ICIs therapy was analyzed from the results of previous clinical trials(MSKCC).Results1.TMB of TP53 and ARID1 A co-mutation group was significantly higher than the other three groups(P<0.05)in TCGA cohort.While in ICGC cohort,TMB of co-mutation group was also significantly higher than TP53 single gene mutation group and wild type group(P<0.05),but it was slightly lower than ARID1 A single gene mutation group and it was not statistically significant.There was also observed to have higher TMB levels of samples with TP53 and ARID1 A co-mutation in our cohort.In exploring the mechanism of TP53 and ARID1 A co-mutation on TMB,it was shown that the difference between the mutation rate of the POLD1 gene during DNA replication and the ATM gene during DNA double-strands break repair between the four groups was consistent with the TMB.2.In TCGA cohort,the proportion of MSI-H was the highest in the TP53 and ARID1 A co-mutation group,which was significantly higher than that in TP53 single gene mutation group and wild type group(P<0.05),but was not significant with ARID1 A single gene mutation group.In our center cohort,one TP53 and ARID1 A co-mutation sample was MSI-H and the other samples were MSS.Analysis of the effects of co-mutation on MRR-related genes showed that differences in the MLH1,MSH2,MSH6,and MMR comprehensive genes’ mutations between the groups were consistent with MSI-H differences,while PMS2 was not significant between co-mutation group and the other three groups.However,protein expression of MSH2 and MSH6 did not differ significantly between the groups.3.ESTIMATE analysis showed that the immune score of TP53 and ARID1 A co-mutation samples were at a medium level,and there was no significant differences with the other three groups.But it was pointed out in CIBERSORT analysis that co-mutation group had higher levels of CD8 + T cells,T cells CD4 + memory,follicular helper T cells and M1 macrophages,especially the content of activated T cells CD4 +memory was significantly higher than that in TP53 single gene mutation group and wild type group(P<0.05).While the differences of other infiltrating immune cells did not reach a significant level.PD-L1 expression was also higher in the TP53 and ARID1 A co-mutation group,which was significantly higher than TP53 single gene mutation group(P<0.05),but no significant difference with the other two groups.4.Survival analysis of 65 patients receiving ICIs therapy showed that 77.8% of patients in the TP53 and ARID1 A co-mutation group did not have an endpoint event at the end of follow-up.And the 1-year survival rate of the TP53 and ARID1 A co-mutation group and the non-comutation group was 44.4% vs 16.1%,and the 2-year survival rate was 11.1% vs 5.4%.But OS extended do not reach the significant level(P=0.168>0.05),and the results of multivariate survival analysis were only marginal significant(P=0.071>0.05).PFS analysis of 28 patients with detailed efficacy evaluation showed that the median PFS of the co-mutation group and the non-comutation group was 14.0 months vs 1.87 months and there was no significant difference in PFS prolongation(P=0.212>0.05).And 5 patients with TP53 and ARID1 A co-mutation received complete tumor remission after ICIs therapy,of which 2 cases had PFS of 14.0 and 15.6 months,and the other case had no tumor progression at the end of follow-up.Conclusion1.TP53 and ARID1 A co-mutation is common in gastric cancer.Co-mutation may affect the repair of DNA double-strand breaks and interfere with the process of DNA replication,which can increase the instability of the genome and lead to an increase in gene mutation rate and tumor mutational burden.It may be sought to be a biomarker for gastric cancer patients receiving ICIs therapy.2.TP53 and ARID1 A co-mutation can increase the mutations of MMR-related genes,especially the mutations of MLH1,MSH2 and MSH6,but it does not affect the mutations of PMS2,which can result in MSI-H.It may not affect the protein expression when the mutation type was missense mutation and the result of immunohistochemistry cannot reflect the status of MMR exactly at that time.3.Patients with TP53 and ARID1 A co-mutation have a certain level of TILs infiltration and PD-L1 expression,which may be benefit from ICIs treatment.4.Gastric cancer patients with TP53 and ARID1 A co-mutation can benefit from ICIs treatment,but it should conbine with other biomarkers when patients without co-mutation. |
