目的:肉瘤是一组具有超过100种不同亚型的高度侵袭性和转移性肿瘤。由于它们的多样性和稀有性,产生预测患者预后的多肉瘤特征具有挑战性.
方法:这里,我们使用多个表观遗传和基因组患者数据集,鉴定了多种肉瘤亚型进展和转移的DNA甲基化特征.恶性周围神经鞘瘤(MPNSTs)是高度转移的肉瘤,经常丢失组蛋白甲基转移酶,PRC2。PRC2的缺失与MPNST转移有关,并在DNA甲基化中起着关键的非规范作用。
结果:我们发现,MPNST中超过900个5'-C-磷酸-G-3'(CpG)被高甲基化,PRC2损失。此外,在两个独立的患者数据集中,我们确定了IL17D/RD家族中与MPNST进展和转移相关的8个差异甲基化CpG.在其他肉瘤亚型中也发现了类似的趋势,包括骨肉瘤,横纹肌肉瘤,和滑膜肉瘤.scRNAseq数据集的分析确定IL17D/RD表达在肿瘤细胞和周围基质群体中都发生。
结论:这些结果可能对肉瘤的临床治疗和监测具有广泛意义。
OBJECTIVE: Sarcomas are a complex group of highly aggressive and metastatic tumors with over 100 distinct subtypes. Because of their diversity and rarity, it is challenging to generate multisarcoma signatures that are predictive of patient outcomes.
METHODS: Here, we identify a DNA methylation signature for progression and metastasis of numerous sarcoma subtypes using multiple epigenetic and genomic patient data sets. Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are highly metastatic sarcomas with frequent loss of the histone methyltransferase, PRC2. Loss of PRC2 is associated with MPNST metastasis and plays a critical noncanonical role in DNA methylation.
RESULTS: We found that over 900 5\'-C-phosphate-G-3\' (CpGs) were hypermethylated in MPNSTs with PRC2 loss. Furthermore, we identified eight differentially methylated CpGs in the IL17D/RD family that correlate with the progression and metastasis of MPNSTs in two independent patient data sets. Similar trends were identified in other sarcoma subtypes, including osteosarcoma, rhabdomyosarcoma, and synovial sarcoma. Analysis of scRNAseq data sets determined that IL17D/RD expression occurs in both the tumor cells and the surrounding stromal populations.
CONCLUSIONS: These results might have broad implications for the clinical management and surveillance of sarcoma.