Identification of potential mutations and genomic alterations in the epithelial and spindle cell components of biphasic synovial sarcomas using a human exome SNP chip.
BACKGROUND
Synovial sarcoma (SS) is one of the most aggressive soft-tissue sarcomas and is noted for late local recurrence and metastasis. It is of uncertain histological origin and exhibits a biphasic histopathological form involving both the mesenchyme and epithelium. Thus, its diagnosis and therapy remain a huge challenge for clinicians and pathologists. This study aimed to determine whether differential morphological-associated genomic changes could aid in ascertaining the histogenesis of SS and to determine whether these sarcomas showed some specific mutated genes between epithelial and spindle cells that would promote tumor invasion and metastasis.


METHODS
We conducted a comprehensive genomic analysis of mesenchymal and epithelial components in 12 formalin-fixed paraffin-embedded biphasic SS samples using the Illumina human exon microarray. Exome capture sequencing was performed to validate the single nucleotide polymorphism (SNP)-chip data, and de novo data were generated using a whole-exome chip with the Illumina exon microarray. Fisher's exact test based on PLINK analysis of the SNP-chip data.


RESULTS
Here, the SNP-chip data showed that 336 SNPs had association P-values of less than 0.05 by chi-square test. We identified 23 significantly mutated genes between epithelial and spindle cell regions of SSs. Fifteen gene mutations were specific for the spindle cell component (65.2 %) and eight for the epithelial cell component (34.8 %). Most of these genes have not been previously reported in SS, and neuroguidin (NGDN), RAS protein activator like 3 (RASAL3), KLHL34 and MUM1L1 have not previously been linked to cancer; only one gene (EP300) has been reported in SS. Genomic analyses suggested that the differential SNPs in genes used for functional enrichment are mainly related to the inflammatory response pathway, adhesion, ECM-receptor interactions, TGF-β signaling, JAK-STAT signaling, phenylalanine metabolism, the intrinsic pathway and formation of fibrin.


CONCLUSIONS
This study investigated novel biological markers and tumorigenic pathways that would greatly improve therapeutic strategies for SS. The identified pathways may be closely correlated with the pathogenic mechanisms underlying SS, and SS development is associated with morphological features.
Department of Oncology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei, 430000, China. qiyanyan-2004@126.com.|Department of Pathology, Shihezi University School of Medicine, North 4th Road, Shihezi, 832002, Xinjiang, China. qiyanyan-2004@126.com.|Key Laboratories for Xinjiang Endemic and Ethnic Diseases, Shihezi University and Chinese Ministry of Education, Shihezi, Xinjiang, 832002, China. qiyanyan-2004@126.com.
Yan
Y
Qi
Department of Pathology, Shihezi University School of Medicine, North 4th Road, Shihezi, 832002, Xinjiang, China. wangning_729@126.com.|Key Laboratories for Xinjiang Endemic and Ethnic Diseases, Shihezi University and Chinese Ministry of Education, Shihezi, Xinjiang, 832002, China. wangning_729@126.com.
Ning
N
Wang
Department of Pathology, Shihezi University School of Medicine, North 4th Road, Shihezi, 832002, Xinjiang, China. ocean123456@163.com.|Key Laboratories for Xinjiang Endemic and Ethnic Diseases, Shihezi University and Chinese Ministry of Education, Shihezi, Xinjiang, 832002, China. ocean123456@163.com.
Li-Juan
LJ
Pang
Department of Pathology, Shihezi University School of Medicine, North 4th Road, Shihezi, 832002, Xinjiang, China. zouhong_patho@163.com.|Key Laboratories for Xinjiang Endemic and Ethnic Diseases, Shihezi University and Chinese Ministry of Education, Shihezi, Xinjiang, 832002, China. zouhong_patho@163.com.
Hong
H
Zou
Department of Pathology, Shihezi University School of Medicine, North 4th Road, Shihezi, 832002, Xinjiang, China. jianming.120@163.com.|Key Laboratories for Xinjiang Endemic and Ethnic Diseases, Shihezi University and Chinese Ministry of Education, Shihezi, Xinjiang, 832002, China. jianming.120@163.com.
Jian-Ming
JM
Hu
Department of Pathology, Shihezi University School of Medicine, North 4th Road, Shihezi, 832002, Xinjiang, China. zhaojin7736@126.com.|Key Laboratories for Xinjiang Endemic and Ethnic Diseases, Shihezi University and Chinese Ministry of Education, Shihezi, Xinjiang, 832002, China. zhaojin7736@126.com.
Jin
J
Zhao
Key Laboratories for Xinjiang Endemic and Ethnic Diseases, Shihezi University and Chinese Ministry of Education, Shihezi, Xinjiang, 832002, China. zhangjunyc@163.com.|Department of Medical Genetics, Shihezi University School of Medicine, Bei-Er-Lu, Shihezi, Xinjiang, 832000, China. zhangjunyc@163.com.
Jun
J
Zhang
Department of Pathology, Shihezi University School of Medicine, North 4th Road, Shihezi, 832002, Xinjiang, China. 342682442@qq.com.|Key Laboratories for Xinjiang Endemic and Ethnic Diseases, Shihezi University and Chinese Ministry of Education, Shihezi, Xinjiang, 832002, China. 342682442@qq.com.
Chun-Xia
CX
Liu
Department of Pathology, Shihezi University School of Medicine, North 4th Road, Shihezi, 832002, Xinjiang, China. zhangwj82@yahoo.com.|Key Laboratories for Xinjiang Endemic and Ethnic Diseases, Shihezi University and Chinese Ministry of Education, Shihezi, Xinjiang, 832002, China. zhangwj82@yahoo.com.
Wen-Jie
WJ
Zhang
Department of Oncology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei, 430000, China. yxl@medmail.com.cn.
Xiang-Lin
XL
Yuan
Department of Oncology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei, 430000, China. lifeng7855@126.com.|Department of Pathology, Shihezi University School of Medicine, North 4th Road, Shihezi, 832002, Xinjiang, China. lifeng7855@126.com.|Key Laboratories for Xinjiang Endemic and Ethnic Diseases, Shihezi University and Chinese Ministry of Education, Shihezi, Xinjiang, 832002, China. lifeng7855@126.com.
Feng
F
Li
D000328:Adult; D002648:Child; D004847:Epithelial Cells / Q000378:metabolism*; D059472:Exome / Q000235:genetics*; D005260:Female; D023281:Genomics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D013584:Sarcoma, Synovial / Q000235:genetics / Q000473:pathology*; D055815:Young Adult