Hou Mingming, Guo Xiaohui, Chen Yu, Cong Lidan, Pan Changwu
Department of Osteo-Surgery, Hainan Cancer Hospital, Haikou, Hainan, China (mainland).
Department of Orthopedics, Zhuhai Center for Maternal and Child Health Care, Zhuhai, Guangdong, China (mainland).
Med Sci Monit. 2020 Dec 28;26:e928400. doi: 10.12659/MSM.928400.
BACKGROUND Soft-tissue sarcomas are a group of heterogeneous and rare mesenchymal tumors with aggressive behavior. We aimed to identify the molecular signatures of N⁶-methyladenosine (m6A) methylation regulators associated with patient prognosis using The Cancer Genome Atlas (TCGA) database. MATERIAL AND METHODS To evaluate the role of m⁶A in soft-tissue sarcomas, genomic and clinical data were downloaded from TCGA. The copy number variations (CNVs) and mutations of m6A regulators were analyzed. RESULTS Alterations of m⁶A regulators were common, and ALKBH5 showed the highest frequency of copy number gain, while ZC3H13 had the highest frequency of loss. CNVs and mutations were closely correlated with histology (P<0.001) and tumor size (P=0.040), and CNVs were correlated with mRNA expression. Furthermore, patients with gains of METTL16, RMB15, RMB15B, YTHDC, and YTHDF3 displayed poorer overall survival (OS), and patients with gains of RBM15 and YTHDC2 and loss of IGF2BP1 had poorer disease-free survival (DFS). Further analysis indicated that CNVs and mutations of KIAA1429, YTHDF3, and IGF2BP1 were independent risk factors predicting OS and DFS. Gain of "writers" with loss of "erasers" led to worse OS than gain of "writers". Genes involved in JAK2 oncogenic signature were enriched in cases of higher expressions of METTL16, YTHDC2, and YTHDF3. Similarly, the core serum response signature was enriched in patients with higher expressions of IGF2BP1, METTL16, RBM15, and YTHDC2. CONCLUSIONS Our study provides a useful molecular tool to predict the outcome of soft-tissue sarcomas and deepens our understanding of the molecular mechanisms of the development of the disease.
软组织肉瘤是一组异质性的罕见间充质肿瘤，具有侵袭性。我们旨在使用癌症基因组图谱（TCGA）数据库确定与患者预后相关的N⁶-甲基腺苷（m6A）甲基化调节剂的分子特征。
为评估m⁶A在软组织肉瘤中的作用，从TCGA下载了基因组和临床数据。分析了m6A调节剂的拷贝数变异（CNV）和突变情况。
m⁶A调节剂的改变很常见，ALKBH5的拷贝数增加频率最高，而ZC3H13的缺失频率最高。CNV和突变与组织学（P<0.001）和肿瘤大小（P=0.040）密切相关，且CNV与mRNA表达相关。此外，METTL16、RMB15、RMB15B、YTHDC和YTHDF3拷贝数增加的患者总生存期（OS）较差，而RBM15和YTHDC2拷贝数增加且IGF2BP1缺失的患者无病生存期（DFS）较差。进一步分析表明，KIAA1429、YTHDF3和IGF2BP1的CNV和突变是预测OS和DFS的独立危险因素。“写者”增加而“擦除者”缺失导致的OS比“写者”增加更差。在METTL16、YTHDC2和YTHDF3表达较高的病例中，参与JAK2致癌特征的基因富集。同样，在IGF2BP1、METTL16、RBM15和YTHDC2表达较高的患者中，核心血清反应特征富集。
我们的研究提供了一种有用的分子工具来预测软组织肉瘤的预后，并加深了我们对该疾病发生分子机制的理解。
