Analysis Of The Association Of NOTCH3 Mutation With The Prognosis Of MCRC Patients Treated With Immune Checkpoint Inhibitors

Objective:Immune checkpoint inhibitors(ICIs)are revolutionizing cancer treatment strategies due to their unique mechanism of action,favorable clinical response,and durable disease control.The clinical guidelines of colorectal cancers(CRCs)recommended ICIs as the first-line treatment option for patients with metastatic colorectal cancer(m CRC),with microsatellite instability-high(MSI-H)and/or defective mismatch repair(d MMR).However,MSI-H/d MMR colorectal cancer cases only represent a small proportion.Searching for new reliable biomarkers and screening out the benefit of ICIs therapy have always been the direction of exploration.This present study utilized publicly accessible data to analyze the correlation between NOTCH3 mutation with the prognosis of m CRC patients treated with ICIs.Aim to demonstrate whether NOTCH3 mutation could be used as a predictive biomarker to predict the response to ICI therapies in m CRC patients.Methods:We accounted for the correlation of NOTCH3 mutation with the outcomes of ICIs treatment in m CRC patients from multiple perspectives.Firstly,we retrieved the m RNA expression data,clinical data,and somatic mutation data of CRC patients from Xena database to perform the differently expressed genes(DEGs)analysis between CRC tissues with or without NOTCH3 mutation and adjacent normal tissues.And then the biological process(BP)enrichment analyses of DEGs were conducted with Web Gestalt.Next,the correlation of NOTCH3 genetic alterations with the expression levels of CTLA-4and PD-L1 and the immune cells infiltration retrieved from x Cell database was evaluated.Another CRC sequencing dataset was retrieved from c Bio Portal database to assess the association of NOTCH3 mutation with the status of MSI-H and TMB.Finally,a treatment data of m CRC patients was retrieved from c Bio Portal to evaluate the correlation of NOTCH3 mutation with the prognosis of patients treated with ICIs.Propensity score matching adjustment method based on multivariable logistic regression model was applied to reduce the influence of confounding variables.Results:We observed that the frequency of NOTCH3 mutation ranged from 2%to 14%and the mean frequency was 7%.The main genetic alterations were missense mutations,splice mutations and truncating mutations.A total of 1217 DEGs were identified between NOTCH3-mutant CRC tissues and normal tissues,of which 786 were up-regulated genes and 431 were down-regulated genes.Compared with the DEGs of NOTCH3-wild-type CRCs,the specifically up-regulated genes of NOTCH3-mutant CRCs mainly involved in the positive regulation of immune responses,and the specifically down-regulated genes mainly involved in the cell metabolism.Besides,NOTCH3-mutant CRCs were accompanied by higher expression levels of CTLA-4 and PD-L1 and higher infiltration levels of immune effector cells compared with those of NOTCH3-wild-type CRCs.And NOTCH3 mutation was closely associated with MSI-H/hypermutated status and the association coefficient(r_n)was 0.466(p<0.001).Finally,survival analysis indicated that NOTCH3-mutant m CRC patients had a better prognosis after ICIs therapy compared with that of NOTCH3-wild-type m CRC patients(mean survival time 35.55 vs.17.03 months;hazard ratio 0.12;95%CI,0.02-0.88;Log-rank P=0.011).Conclusions:After PSM,NOTCH3-mutant m CRC patients could benefit from ICIs therapy both mechanistically and therapeutically.Therefore,NOTCH3 mutation could be used to the identification of patients that more likely to benefit from ICIs therapy in advanced colorectal cancers.