Primary Renal Synovial Sarcoma:A Case Report,Mutation Landscape And Intra-tumor Heterogeneity Analysis

Background and objective:Synovial sarcoma(SS),a rare type of soft tissue tumor with high degree of malignancy,accounts for 7%--10%of soft-tissue sarcoma.Synovial sarcoma usually arise from joints,extremities and etc.However primary SS arising from kidney is extremely rare in clinical practice.Primary renal synovial sarcoma represents a diagnostic challenge.They are not only rare,but also exhibits similar clinical features with other renal cell carcinoma types.Due to few cases reported publicly,yet there are no universally recognized imaging features for preoperative diagnosis.For now,the main therapeutic strategy for primary renal synovial sarcoma is still surgical extirpation and aggressive management with combination of surgical resection and chemotherapy is also reported.However no authoritative clinical guidelines have been developed to provide advice for clinical treatment.It is reported that patients with primary renal synovial sarcoma and metastatic sites received chemotherapy and the short-term follow up is satisfied.However,it is too early to draw a conclusion whether patients benefit from chemotherapy because of lack of epidemiologic evidence to support it.Based on studies reported,adriamycin or epirubicin combined with ifosfamide is mainly regarded as the first-chemotherapy strategy,but no clear epidemiologic results to estimate the efficacy of chemotherapy...Recent years,with advance of high-throughput sequence technology,gene detection is broadly used in clinically practice.High-throughput sequence is able to detect several types of variation among genome,which enable us to not only establish genomic landscape but also perform bioinformatic analysis on sequencing results.That would provide more comprehensive information for clinician to make precise and personalize medical strategy.As far as we know,there are no reports focused on RSS genomic landscape and intra-tumor heterogeneity.Since it has been reported that sunitinib(an EGFR inhibitor)could be administered in a group of patients with primary renal synovial sarcoma,it is not suit for all.Therefore,giving a comprehensive view of mutation landscape and exploring targets with therapeutic potential would provide novel therapeutic strategies.Meanwhile clinician with a comprehension of intra-tumor heterogeneity will make complete and perfect strategiesMethods:In this study,we present a case of a 58-year old female patient diagnosed as primary renal synovial sarcoma.After surgical resection,the histopathology test was performed for pathologic diagnosis.Immunohistochemistry and fluorescence in situ hybridization(FISH)were also performed for further confirmation.We collected 5 spatially distinct samples from the tumor(RSS1,RSS2,RSS3,RSS4 and RSS5).RSS1 and RSS2 came from the cyst wall.RSS3,RSS4 and RSS5 came from different site of the inner mass.Hematoxylin-eosin staining was performed on all of the tissues followed by observation under microscope.We also collected the peripheral blood of the patient before surgery and conducted whole-exome sequencing(WES)on 5 RSS samples and blood sample.After quality control,bioinformatic analysis was performed to establish RSS genetic mutation landscape.Meanwhile,comparing results from 5 spatially distinct samples,the intra-tumor heterogeneity was analyzed.Results:Pathological evaluation indicated the diagnosis of synovial sarcoma,and immunohistochemistry showed positive staining for CD99,EMA and TLE1,but negative for CD34,BCL-2,CK,CK7,Desmin,MyoDl,Myogenin and SMA.Besides,SYT-SSX gene fusion was confirmed by FISH.Whole-exome sequencing results showed that 10 indels and 502 single nucleotide variants(SNVs)were identified in RSS1 and RSS2.92 indels and 1128 single nucleotide variants(SNVs)were identified in RSS3,RSS4 and RSS5.Besides,the distribution of indels and SNVs is varied between samples from cyst wall and inner mass.Although the SNVs signature is also varied,the C>T/G>A signature is mostly frequent in all 5 samples.Meanwhile analysis on copy number variations(CNVs)showed that MIR621,MUC5B,MUC6,PI4KAP1,SLC25A15,SSC5D,TPTE2P5 were shared by 4 samples.In order to interpret the potential functional biological impact of the somatic variants and explore their function in origination and development of this neoplasm,we annotated them to highlight those falling in predisposing genes.14 genes were finally confirmed.Among them,9 genes were classified as missense mutation.Compared somatic mutations of regional samples with known driver genes,we identified 5 genes(ZNF521?ROS1?ASXL1?DHX9 and DFFB)as possible driver mutation in RSS.Using PyClone analysis to investigate the cellular prevalence of each variant among between samples from two components,the result indicated the changing subclonal composition between samples from spatially different positions.Phylogenetic tree analysis revealed branching rather than linear tumor evolution in this RSS.Administration of target drugs based on the results from gene detection enable clinician to make clinical strategies meeting the requests of precised medicine.And that would also provide possible drugs for sequent therapy.However,the results showed that there were no sensitive or resistant gene mutation existing in EGFR,KRAS and PIK3CA.Conclusion:In this study,we first used high-throughput sequence technology to establish mutation landscape of primary renal synovial sarcoma.The intra-tumor heterogeneity was identified in RSS,especially in sample from different position.We also identified 5 possible driver genes,which might provide revelation for sequent studies in RSS.