Department of Orthopaedic Surgery, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
Foundation Medicine, Cambridge, MA, USA.
Commun Biol. 2022 Mar 8;5(1):213. doi: 10.1038/s42003-022-03117-1.
Aberrant methylation of genomic DNA has been reported in many cancers. Specific DNA methylation patterns have been shown to provide clinically useful prognostic information and define molecular disease subtypes with different response to therapy and long-term outcome. Osteosarcoma is an aggressive malignancy for which approximately half of tumors recur following standard combined surgical resection and chemotherapy. No accepted prognostic factor save tumor necrosis in response to adjuvant therapy currently exists, and traditional genomic studies have thus far failed to identify meaningful clinical associations. We studied the genome-wide methylation state of primary tumors and tested how they predict patient outcomes. We discovered relative genomic hypomethylation to be strongly predictive of response to standard chemotherapy. Recurrence and survival were also associated with genomic methylation, but through more site-specific patterns. Furthermore, the methylation patterns were reproducible in three small independent clinical datasets. Downstream transcriptional, in vitro, and pharmacogenomic analysis provides insight into the clinical translation of the methylation patterns. Our findings suggest the assessment of genomic methylation may represent a strategy for stratifying patients for the application of alternative therapies.
异常的基因组 DNA 甲基化已在许多癌症中报道。已经表明，特定的 DNA 甲基化模式可提供具有临床意义的预后信息，并定义具有不同治疗反应和长期预后的分子疾病亚型。骨肉瘤是一种侵袭性恶性肿瘤，大约一半的肿瘤在接受标准联合手术切除和化疗后复发。目前除了辅助治疗的肿瘤坏死外，尚无公认的预后因素，传统的基因组研究迄今为止未能确定有意义的临床关联。我们研究了原发性肿瘤的全基因组甲基化状态，并测试了它们如何预测患者的结局。我们发现相对基因组低甲基化与对标准化疗的反应有很强的预测性。复发和生存也与基因组甲基化有关，但通过更特定于位点的模式。此外，这些甲基化模式在三个小的独立临床数据集之间是可重复的。下游转录、体外和药物基因组学分析为甲基化模式的临床转化提供了深入的了解。我们的研究结果表明，评估基因组甲基化可能代表了一种对患者进行分层以应用替代治疗策略的方法。
