Qi Yan, Wang Ning, Pang Li-Juan, Zou Hong, Hu Jian-Ming, Zhao Jin, Zhang Jun, Liu Chun-Xia, Zhang Wen-Jie, Yuan Xiang-Lin, Li Feng
Department of Oncology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei, 430000, China.
Department of Pathology, Shihezi University School of Medicine, North 4th Road, Shihezi, 832002, Xinjiang, China.
BMC Med Genomics. 2015 Oct 27;8:69. doi: 10.1186/s12920-015-0144-7.
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.
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.
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.
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.
滑膜肉瘤（SS）是最具侵袭性的软组织肉瘤之一，以局部复发晚和转移而闻名。其组织学起源尚不确定，呈现出涉及间充质和上皮的双相组织病理学形式。因此，其诊断和治疗对临床医生和病理学家来说仍然是巨大的挑战。本研究旨在确定形态学相关的基因组差异变化是否有助于确定滑膜肉瘤的组织发生，以及这些肉瘤在上皮细胞和梭形细胞之间是否显示出一些促进肿瘤侵袭和转移的特定突变基因。
我们使用Illumina人类外显子微阵列对12个福尔马林固定石蜡包埋的双相滑膜肉瘤样本中的间充质和上皮成分进行了全面的基因组分析。进行外显子捕获测序以验证单核苷酸多态性（SNP）芯片数据，并使用Illumina外显子微阵列的全外显子芯片生成从头数据。基于SNP芯片数据的PLINK分析进行Fisher精确检验。
在此，SNP芯片数据显示，通过卡方检验，336个SNP的关联P值小于0.05。我们在滑膜肉瘤的上皮细胞和梭形细胞区域之间鉴定出23个显著突变的基因。15个基因突变是梭形细胞成分特有的（65.2%），8个是上皮细胞成分特有的（34.8%）。这些基因中的大多数以前在滑膜肉瘤中未被报道，神经导向蛋白（NGDN）、RAS蛋白激活剂样3（RASAL3）、KLHL34和MUM1L1以前未与癌症相关联；只有一个基因（EP300）在滑膜肉瘤中被报道过。基因组分析表明，用于功能富集的基因中的差异SNP主要与炎症反应途径、黏附、细胞外基质-受体相互作用、TGF-β信号传导、JAK-STAT信号传导、苯丙氨酸代谢、内在途径和纤维蛋白形成有关。
本研究调查了新的生物标志物和致瘤途径，这将大大改善滑膜肉瘤的治疗策略。所鉴定的途径可能与滑膜肉瘤的发病机制密切相关，并且滑膜肉瘤的发展与形态学特征有关。
