Genomics Investigation Of Liver Metastases From Colorectal Neuroendocrine Neoplasms & Development And Validation Of A Nomogram Based Prognostic Evaluation Model For Sarcomatoid Hepatocellular Carcinoma

Objectives Neuroendocrine tumors are a type of tumor derived from diffuse neuroendocrine cells,which are more common in the digestive system and respiratory tract With the continuous advancement of detection technology and the deepening of people's understanding of neuroendocrine tumors,especially in developed countries,more and more neuroendocrine tumors are diagnosed.According to related research,colorectal neuroendocrine neoplasms have a higher incidence of gastrointestinal neuroendocrine tumors,and some patients with colorectal neuroendocrine neoplasms have liver metastases at the early stage of the tumor,which has caused great problems for subsequent treatment.The purpose of this study was to map the gene map of colorectal neuroendocrine neoplasms by using all exon gene detection and sequencing technology,and further explore the genomics characteristics of colorectal neuroendocrine neoplasms with liver metastasis.Methods From January 1999 to December 2019,50 patients(27 patients with liver metastasis and 23 patients without liver metastasis)with colorectal neuroendocrine neoplasms were treated in Cancer Hospital of Chinese Academy of Medical Sciences and Zhongshan Hospital Affiliated to Fudan University In order to find out the high frequency mutation gene and compare the mutation characteristics between the liver metastasis group and the non liver metastasis group.Results A total of 2999 significant mutations were detected in 50 cases of colorectal neuroendocrine neoplasms.In general,the median mutation of colorectal neuroendocrine neoplasms was 21.The mutation pattern was mainly C>T,G>A.Wilcoxon rank sum test was used to compare the number of mutations in liver metastasis group and non liver metastasis group,P value was 0.006586.There was significant statistical difference.The frequency of gene mutation in TP53,APC,EIF3A,RNF43,KMT2D,ASTN1,DNAJC16,DNHD1,FAT4 was higher than that in non liver metastasis group.The frequency of gene mutation in liver metastasis group was significantly higher than that in non liver metastasis group.The mutation characteristics of all samples were analyzed,and a total of three mutation signatures were obtained,and it was suggested that the AID/APOBEC family may be involved in the development of colorectal neuroendocrine neoplasms.The hepatic metastasis group was more prone to loss of heterozygosity than the non-hepatic metastasis group.Conclusions The mutation pattern of colorectal neuroendocrine neoplasms is mainly C>T,G>A,and the tumor burden of patients with liver metastasis is significantly higher than that of non-hepatic metastasis group.And the hepatic metastasis group is more prone to loss of heterozygosity than the non-hepatic metastasis group.According to the analysis of mutation signatures in the liver metastasis group and the non-hepatic metastasis group,the AID/APOBEC family may play a role in the process of liver metastasis of colorectal neuroendocrine neoplasms.The frequency of TP53,APC,EIF3A,RNF43,KMT2D,ASTN1,DNAJC16,DNHD1,FAT4 in colorectal neuroendocrine neoplasms is relatively high.8%and more samples have such genetic mutations.The frequency of gene mutation was significantly higher than that in the non-hepatic metastasis group.Objectives Sarcomatoid hepatocellular carcinoma(SHC)is a rare subtype of liver cancer with extremely poor prognosis.This study aimed to identify prognostic factors and to develop an exclusive and efficient nomogram to predict the cancer specific survival(CSS)for SHC.Methods Patients diagnosed with SHC from January 1,1973 to December 31,2015 were assessed from Surveillance,Epidemiology,and End Results(SEER)database and identified as the training cohort.Lasso and Cox proportional hazards regression were used to identify prognostic risk factors and construct a nomogram.Tumor size was empirically included in the PEM.The predictive accuracy and discriminative ability of the nomogram were determined by concordance index(C-index),calibration curve and receiver operating characteristic curve(ROC).Decision curve analysis(DCA)compared the clinical benefits of the prognostic evaluation model(PEM)with AJCC stage system.The results were validated with an external validation cohort of 19 SHC patients from the Cancer Hospital,Chinese Academy of Medical Sciences.Results A total of 116 SHC patients were included in the training cohort.Multivariate Cox analysis revealed M stage(distant metastasis),primary tumor surgery,chemotherapy to be associated with CSS and along with tumor size an integrated PEM was constructed.Calibration curve for probability of survival showed good agreement between the nomogram and actual observation.The C-index of the nomogram for predicting CSS was 0.853(95%CI 0.826 to 0.880),which was statistically higher than that of American Joint Committee on Cancer(AJCC)sixth edition(0.649,95%CI 0.613 to 0.685;P<0.0001).In the validation cohort,C-index value of the PEM's discrimination(0.794)was better than the Barcelona Clinic Liver Cancer(BCLC)(0.722),Clip score(0.69)and Okuda(0.495;P<0.005 for all)staging system,and no statistical difference was found with AJCC eighth edition(0.784)and Izumi(0.822;P>0.2 for all).Conclusion The proposed 4-factor nomogram of PEM could accurately predict the prognosis of SHC,and could be used in clinical practice.