The Pathology Of Prostate Cancer Patients With Metastases And Preliminary Exploration Of Its Mechanism:An Analysis From 16744 Patients

BackgroundProstate cancer is a common tumor of the male,with high morbidity and mortality.Metastasis is one of the leading causes of death for patients with prostate cancer.Current research shows that androgen deprivation therapy and chemotherapy are beneficial for patients with metastatic prostate cancer,and the value of radiation therapy and surgery is still controversial.Besides,sites of synchronous distant metastases and their impacts on prognosis in prostate cancer patients are still unclear.Tumor metastasis is a multi-step process,for instance,endothelin 1,bone morphogenetic protein,TGF?2,and vascular endothelial growth factor take part in the metastases of prostate cancer.However,the mechanism of prostate cancer metastasis has not been fully elucidated.ObjectivesTo investigate the sites of synchronous distant metastases and prognosis in patients with newly diagnosed prostate cancer(PCa)with bone metastases,which may be benefit for assessing the prognosis;to explore the risk factors of patients with prostate cancer metastasis in order to assess the risk of patient metastasis;to explore the mechanism of prostate cancer metastasis.Methods(1)The Surveillance,Epidemiology,and End Results(SEER)database of the National Cancer Institute was used for the analysis.Based on the criteria,16,643 de novo PCa patients with bone metastases were included.Then,we extracted basic information: including demographic data(e.g.age)and tumor information(e.g.metastasis,PSA,Gleason score,survival time,survival status,etc.);After stratification of metastatic sites(bone,lung,liver,and brain)and treatment modalities,overall survival(OS)and independent predictors of OS,were analyzed by Kaplan-Meier survival and univariate and multivariate Cox regression analysis.(2)Collect data of patients with prostate cancer from the First Affiliated Hospital of Zhejiang University School of Medicine from January 2011 to October 2015,and analyze the clinicopathology characteristics of patients with metastatic prostate cancer and those without metastasis.The risk factors of prostate cancer metastasis were determined by logistic regression analysis.(3)The GSE21034-GPL5188 data-set in the gene expression database were selected for the analysis of mechanism of metastasis,which contains 131 patients with primary prostate cancer and 19 patients with bone metastases.Then differential gene analysis of the two groups were performed.KEGG pathway analysis and GO pathway analysis were performed by DAVID.Expression validation and prognosis analysis were performed on new data-sets: Oncomine,TCGA and GSE70770.ResultsBy analyzing data of 16643 patients with bone metastases from prostate cancer,we found that the incidence of bone metastases are increased year by year;the average age of patients with bone metastases from prostate cancer was 71 years,and the degree of malignancy of bone metastases was high.For example,,the Gleason score for most patients are 8-10,PSA > 50 ng/ml accounts for majority.Only bone metastases accountfor 90%,and bone metastases accompanied with other metastases account for only about 10%.Among multiple metastases,bone metastases with lung metastases are the most common and the prognosis is relatively good(median survival time: 20 months),only poorer than only bone metastasis(median survival time: 27 months);bone metastases with liver metastasis have the worst prognosis(median survival time: 10months).Only 9.6%,22.4%,and 13.3% patients treated with surgery,radiotherapy and chemotherapy;surgery,radiation therapy,and chemotherapy all improved the prognosis of patients with only bone metastases,but for patients with bone metastases and other metastases,only chemotherapy could improve their prognosis;radical prostatectomy(HR: 0.339;95% CI: 0.0.231–0.495;p <0.001)and brachytherapy(HR: 0.567;95% CI:0.388–0.829;p = 0.003)have significant survival benefits for patients with only bone metastases.Age> 70 years,unmarried,PSA> 50 ng / ml,Gleason score of 8-10 points,bone metastasis with other metastatic sites were associated with poor overall survival(p<0.01).By analyzing 1935 non-metastatic prostate cancer and 101 patients with metastatic prostate cancer in our hospital,we found that total PSA,free PSA,free / total PSA ratio,Gleason score,serum Ferritin,Gamma-glutamyl transpeptidase was significantly higher in non-metastatic patients(all p <0.05),while Direct Bilirubin and Indirect Bilirubin were significantly lower in non-metastatic patients(all p <0.05).Multivariate logistic regression analysis showed that PSA level,Gleason score and serum Ferritin were independent risk factors for prostate cancer metastasis,while high-density lipoprotein was a protective factor for metastasis.By bioinformatics analysis,we compared the patients with primary prostate cancer and patients with metastatic prostate cancer,and found 184 up-regulated genes and 1199down-regulated genes in metastasis prostate cancer,of which ACTG2(actin gamma 2,smooth muscle)was most significant down-regulated in metastasis prostate cancer.Furthermore,this down-regulation has been validated in other databases such as TheCancer Genome Atlas(TCGA),Oncomine,and GSE70770.Kaplan-Meier survival curve and multivariate Cox regression analysis further confirmed that low expression of ACTG2 was associated with poor prognosis in patients with prostate cancer.ConclusionLung metastasis is the most common metastasis,following bone metastasis;liver metastases patients have poor prognosis.Surgery,radiation therapy and chemotherapy can improve the prognosis of patients with only bone metastases However,for patients with bone metastases accompanied by other metastases,only chemotherapy can improve their prognosis.Radical prostatectomy and brachytherapy improved OS in patients with only bone metastases.Metastatic sites,age,race,marital status,PSA level,and Gleason score were independent prognostic factors for metastasis prostate patients.PSA level,Gleason score and serum Ferritin were independent risk factors for prostate cancer metastasis,while high-density lipoprotein was a protective factor for metastasis.Regarding the mechanism of prostate cancer metastasis,ACTG2 is significantly related to prostate cancer metastasis status and related to the prognosis of prostate cancer,and may be used as a biomarker for prostate cancer metastasis and poor prognosis.