The Heterogeneity And Genomic Variation In Different Tumor Cell Populations Of Ovarian Cancer Tissue

Background:Ovarian cancer is one of the most common malignant tumors in gynecology,which accounts for 15% of all gynecologic malignancies.It is difficult to early diagnosis,while has high mortality and poor prognosis.The 5 year survival rate can not be improved due to tumor recurrence and drug resistance.Recently,with the improvement of gene technology,more and more researchers began to query that whether cancer is a homogeneous “clone population” of malignant cells.Tumor heterogeneity refers to tumor evolution and adaptation during the process of tumor occurrence,development and metastasis.Tumor is gradually transformed from monoclonal to poly-clonal state.In different sub-clones of the tumor cells,there are many directions,in different morphology,antigen expression,biological behavior and even transmission of genes.Thus,there is a high heterogeneity in tumor,which make tumor evolves under the pressure of external environment.This heterogeneous evolution process is closely related to cancer metastasis,drug resistance and clinical prognosis.Tumor heterogeneity makes the personalized medicine really important for the treatment of cancer.However,we have known quite few about the gene heterogeneity and evolution process of ovarian cancer till now.Purposes: Exon capture and next generation high-throughput sequencing technology were used to sequence the tumor and normal tissues,and the specific mutation sites of different ovarian cancer cell groups were screened.High throughput point mutation assay was used to analyze the genetic differences among different tumor cell populations.Analyze the genetic heterogeneity between tumor cells in different parts and tumor cells at different time points of the same body.Constructed the tumor evolution tree model in some of the included patients to find the causes of the formation of different heterogeneous subsets,the characteristics of molecular phenotype,and gene mapping related to tumor metastasis,recurrence and prognosis.Methods: A total of 25 patients with serous ovarian carcinoma(SOC)were enrolled.There were two parts in this trial.The first part included 10 patients defined as platinum-sensitive(5)or platinum-resistant(5)recurrent group.We compared the difference between primary tissues and relapsed tissues.The second part enrolled 15 patients with significantly different OS(8 more than 5 years,while 7 less than 2years).Primary tissues and metastases at diagnosis were collected.Exon capture and next generation sequencing technology were performed to detect the normal tissues and tumor tissues,and screen the specific gene mutations in cancer tissues.Somatic mutations were used to reconstruct the phylogenetic tree model,and analyze the genomic heterogeneity.Results:TP53 mutations were detected in all the samples.In general,the heterogeneity of the hetero metastases was much more obvious than that of the simultaneous metastases.For the recurrent foci,the heterogeneity of the relapse group was higher.However,the difference was not significant between the two groups.The gene copy number variations was higher in the drug resistant relapse group.And in the recurrent foci,there was more chance to find the mutation in BRAF(2/5),NF1(2/5)and PTCH2(2/5),and other genes.We did not find any correlation between the simultaneous metastases and prognosis.However,germline mutations in BRCA1 were more common in the group with better prognosis.Conclusions:Tumor heterogeneity was related to the prognosis of patients.Genetic analysis could be used to predict the prognosis of patients with ovarian cancer,and should be valuable in clinical application.