Clinical Characteristics Of Castleman Disease And Significance Of Somatic Alterations For Idiopathic Multicentric Castleman Disease

ObjectivesCastleman’s disease(CD)is a group of highly heterogeneous lymphoproliferative diseases.Based on the number of the involved lesion,CD can be divided into unicentric CD(UCD)and multicentric CD(MCD).According to the infection status of human herpesvirus-8(HHV-8),MCD further can be divided into HHV-8 associated MCD and HHV-8 negative MCD,the latter of which is also named as idiopathic MCD(iMCD).The long-term survival can be achieved in UCD patients by complete surgical resection of the lesion.At the same time,HHV-8 associated MCD can be effectively treated with the combination of antiretroviral and rituximab based regimens.However,the pathogenesis of iMCD is unknown and its clinical prognosis is poor.Thus,the purpose of this study is to analyze the clinical characteristics of CD and take advantage of whole exome sequencing(WES)to find out the relationship between the gene mutation and the prognosis of iMCD.MethodsWe collected the clinical data of 110 patients diagnosed as CD in The Fisrt Affiliated Hospital of Zhejiang University from January 2007 to December 2017.HHV-8 status was determined based on the results of latency-associated nuclear antigen immunocytochemistry(IHC)on pathological tissue sections.HHV-8 negative MCD would be diagnosed as iMCD according to the consensus diagnostic criteria.WES was performed in these iMCD patients.The association analysis of the sequencing results and clinical data was performed to find to found out the relationship between gene mutation and prognosis.ResultsThe median age of onset was 42 years(range: 11-76 years).Among these patients,82 cases(74.5%)were diagnosed as UCD and 28 cases(25.5%)were diagnosed as MCD.More than half(62.2%)of UCD patients had no symptom at the time of diagnosis,while most of MCD patients had B symptoms(fever,night sweat or weight loss)(P < 0.001).The main pathological type of UCD and MCD was hyaline vascular type and was plasma cell type,respectively.Their 5-year overall survival(OS)rates were 92.9% and 59.3% respectively.The results of clinical data analysis showed that the baseline of clinical characteristics,such as age,gender,B symptoms,hepatomegaly and/or splenomegaly,pleural and/or peritoneal effusion,pathological type,ECOG score and treatment regimen had no significant effect on the OS of the iMCD.According to whether the survival time reached 24 months,patients with iMCD were further divided into OS24 achieved group and OS24 failure group.The analysis results showed that there was also no statistical difference in age,gender,B symptoms,hepatomegaly and/or splenomegaly,pleural and/or peritoneal effusion,pathological type,ECOG score and treatment.A total of 7195 non synonymous mutations(mean: 327,range: 119-1071)were detected by WES.Through the analysis of odds ratio and survival,we found that 5 somatic mutations(NCOA4,DARS2,MTCL1,RABPE1 and DNAH11)might be related to poor prognosis.These somatic mutations can be used as prognostic indicators of iMCD.Interestingly,the single nucleotide mutation of NOCA4 was located in the same position(L261F)in 4 patients.Homology modeling showed that the three-dimensional structure of the NCOA4 protein was changed by L261 F mutation.Meanwhile,western blot showed that the expression of NOCA4 protein was up-regulated in L261 F mutation group.In conclusion,NOCA4 gene mutation may play an important role in the pathogenesis of iMCD.ConclusionCD is a group of high heterogeneity diseases.UCD and MCD patients are different in the clinical manifestations,pathological classification and survival time.Five somatic mutations,including NCOA4,DARS2,MTCL1,RABPE1 and DNAH1,could be used as biomarkers to evaluate the prognosis of iMCD.And mutations of NCOA4 may play an important role in the pathogenesis of iMCD.