| Background and Objectives:Bone and soft tissue sarcoma BSTS are rare malignant tumors of tissues other than bone or cartilage originating in the mesenchymal,such as fat,fascia,muscle,fibers,lymph,and blood vessels.Each subtype has different histological and biological characteristics and different tendency to local infiltration,hematogenous and lymphatic metastasis,and lung metastasis is more common.BSTS account for 1% of all adult malignant tumors and have more than 100 different histologic subtypes,including liposarcoma,leiomyosarcoma,angiosarcoma,epithelioid sarcoma,rhabdomyosarcoma,synovial sarcoma,and clear cell sarcoma.Soft tissue sarcomas can occur anywhere,mainly in the trunk,extremities,and retroperitoneum.According to the incidence rate of different parts of the body,the lower limb,trunk,head and neck,upper limb,posterior peritoneum can also appear liposarcoma and fibrosarcoma,about 75% of the lesions in the extremities(most commonly in the thigh).The incidence of this disease is higher in the elderly and there is no significant gender difference.Soft tissue sarcomas are mostly malignant.Tumor types vary at different ages.The overall incidence of the disease is low,but advanced metastatic patients usually lack effective treatment,have a poor prognosis,and a high mortality rate of about 1% of adult malignant tumors.However,with the progression of the disease,nearly half of adult patients with soft tissue sarcoma develop metastasis,and the prognosis is poor.The 2-year survival rate of patients with distant metastasis is only 30%.The treatment of BSTS mainly includes surgical excision,radiotherapy and chemotherapy combined with targeted therapy,and the prognosis of patients is significantly improved.However,about 20%-30% of patients with distant metastasis are diagnosed with BSTS,and the 2-year survival rate of these patients is less than30%.As a result,it is difficult for traditional therapies to achieve ideal results in patients with metastasis,and it is difficult to accurately evaluate the prognosis of these patients.Therefore,the exploration of the genes and molecular mechanisms underlying the development of BSTS and distant metastasis,as well as the identification of effective targeted therapies and prognostic biomarkers,may provide more ways to further overcome the current clinical difficulties.For example,studies of molecular and biochemical prognostic factors indicate that loss of expression of Rb(retinoblastoma tumor suppressor protein),high expression of p53 and Ki-67(indicating rapid cell division),and non-diploid DNA content(indicating major chromosomal abnormalities)are associated with poor prognosis of BSTS.At the same time,the microenvironment in which tumor cells grow and develop also plays an important role in the occurrence,progression and distant metastasis of tumors.Tumor is composed of a complex tumor micro-environment,including not only parenchymal tumor cells,but also extracellular matrix and other cells.These cells can not only secrete various cytokines,chemokines,growth factors,inflammatory factors and promote the generation of new blood vessels,but also interact with extracellular matrix to jointly change the tumor microenvironment,so as to regulate the occurrence and development of tumors and even distant metastasis.Therefore,by analyzing the heterogeneity and complexity of tumor microenvironment and focusing on the changes of extracellular matrix and the molecular mechanism behind it,the immune characteristics of different tumors can be identified,and the ability to guide and predict immunotherapy response can be improved,and it is beneficial to search for new therapeutic targets.Methods:This project aims to start with the genes and molecular mechanisms related to BSTS prognosis and metastasis,analyze and evaluate the genes,extracellular matrix and related immune characteristics related to BSTS prognosis and metastasis prognosis,and further explore the tumor microenvironment related genes that regulate the progression and metastasis of BSTS and their potential mechanisms.This study provides a new theoretical basis for the diagnosis,prognosis evaluation and treatment of BSTS.At the same time,we aim to construct a prognostic model based on the features of BSTS metastasis and explore the clinical significance of this prognostic model in clinical patients.Research methods:By integrating and analyzing the m RNA chip data of related BSTS in GEO,Gene Expression Omnibus,and combining with the clinical data,we divided them into metastatic group and non-metastatic group,which contain a total of 54613 m RNA expression profiles.DESeq(differential expression analysis)and Limma R package(gene chip expression matrix analysis)were used to screen out the differentially expressed genes(DEGs)between the two groups.We further performed univariate Cox survival analysis of differentially expressed genes,and screened out a total of 5 genes associated with prognosis.On this basis,the least absolute shrinkage and selection operator LASSO and multi-factor Cox regression analysis were used to construct a prognostic model(BSTS Score)to evaluate the effect of its clinical evaluation on BSTS.Finally we validated the prognostic model on the American Cancer patient database.The gene profile and clinical information of patients with external BSTS in the Cancer Genome Atlas(TCGA,The Cancer Genome Atlas)were used to verify the prognostic model and the different expression genes.Then the function,pathway and immune infiltration of the Genes were analyzed using GO analysis(differential proteomics protein function analysis)and KEEG(Kyoto Encyclopedia of Genes and Genomes)to validate the mechanism under the prognosis model jointly.Finally,tumor specimens from clinical patients were collected and immunohistochemical(IHC)analysis was used to verify the prognostic effect of genetic markers in clinical patients.Results:Result: By analyzing the differential expression of genes in patients with metastasis,we obtained five differentially expressed genes associated with the occurrence,development and the distant metastasis of BSTS and constructed a prognostic model of BSTS,which was verified in external patient sequences.Further analysis of related functions and pathways showed that there were significant changes in tumor cell dry,extracellular matrix(ECM)and cell adhesion related pathways between the two risk groups.And it has obvious influence on the survival of BSTS.At the same time,our group emphasized the activation of PI3K-Akt pathway in high-risk patients through pathway enrichment analysis,suggesting that treatment targeting PI3K-Akt pathway may play a role in patients with high-risk BSTS.As the risk score changed,so did the immune infiltration.Finally,immunohistochemical staining(IHC)of tumor samples from clinical BSTS patients confirmed the prognostic role of gene markers in a single subtype of sarcoma.Conclusions:Our study develops and validates a prognostic model based on BSTS metastasis,which can reliably predict the survival of BSTS patients,and provides a possible molecular mechanism and related pathways for this model.These findings may help to make a more accurate evaluation of BSTS patients in the future,and to develop the best individualized treatment plan based on the molecular mechanisms and pathways discovered in this study. |
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