Correlation Analysis Of Tumor Mutation Burden And The Prognosis Of Colorectal Cancer Patients With KRAS Mutation

BackgroundColorectal cancer(CRC)is a common gastrointestinal malignant tumor,ranking as the third most common cancer with the second highest cancer-related mortality rate in the world.Immunotherapy is an important treatment for patients with CRC.However,many patients nonetheless have poor therapeutic outcomes during clinical treatment.The availability of biomarkers for evaluating immunotherapy response in CRC patients is still limited to date.Therefore,there is a clear need to identify predictive biomarkers to guide CRC treatment.Tumor mutation burden(TMB)is defined as the total number of somatic coding errors,base substitutions,and indel mutations found per million bases of DNA,thought to be a key driver of the formation of immunogenic new peptides on the major histocompatibility complex(MHC)of tumor cells,which can affect the response to immune checkpoint inhibitors(ICIs)of patients.Moreover,TMB is a potential prognostic indicator for numerous malignancies.However,to date,there are few reports on the correlation between TMB level and the prognosis of patients with CRC;this study investigated the prognostic value of TMB in CRC to provide a reference for clinical work.MethodsThis study analyzed clinical and somatic mutation data of patients with CRC from the Memorial Sloan Kettering Cancer Center(MSKCC)and The Cancer Genome Atlas(TCGA)cohort.The maftools software package in R software was used to visualize genetic landscape.Kaplan-Meier method was used to construct a survival curve,and Log-rank test was used to analyze the effect of specific somatic mutation genes on the prognosis and the predictive value of TMB level for patients with CRC.Cox univariate and multivariate regression analysis were used to verify whether TMB was an independent prognostic factor for CRC patients with KRAS mutation.And the data from 674 CRC patients with KRAS mutation were randomly divided into the training group and the validation group in a ratio of 7:3.A nomogram prognostic model was established based on the data of the training group,and the model was evaluated using C index,calibration curve and decision curve.ResultsAmong CRC patients,overall survival(OS)was longer in patients with APC mutation than wild-type APC patients(HR=0.65,95%CI:0.51-0.83 P<0.001).OS in CRC patients with KRAS mutation was shorter than those with wild-type KRAS(HR=1.30,95%CI:1.07-1.58,P=0.008).Compared to wild-type,PIK3CA and TP53 mutations had no statistical differences in OS of CRC patients(P>0.05).For all included patients,there was no statistical differences in OS between the high and low TMB groups(P>0.05).However,for patients with KRAS mutations,the high TMB group had longer OS than the low TMB group(HR=0.58,95%CI:0.40-0.83,P=0.013).Cox multivariate regression analysis showed that TMB was an independent prognostic factor for CRC patients with KRAS mutations(HR=0.59,95%CI:0.38-0.93,P=0.023).The C-index of the nomogram was 0.620(95%CI:0.591-0.650),and the correction curve was in good agreement with the prediction results.The prognosis model had high accuracy.ConclusionThis study confirms that high TMB indicates a better prognosis in CRC patients with KRAS mutation.And based on the database information,the prognostic model of CRC patients with KRAS mutation is established in this study,which is helpful to guide clinicians to carry out individualized treatment of CRC patients with KRAS mutation,and has great clinical application value.