Dong Zheng, Zhou Hongyu
Centre for Molecular Medicine and Therapeutics, British Columbia Children's Hospital Research Institute, University of British Columbia, V5Z 4H4, Vancouver British Columbia, Canada.
Genome Science and Technology Graduate Program, University of British Columbia, V5Z 4S6, Vancouver British Columbia, Canada.
Exp Hematol Oncol. 2022 Nov 8;11(1):89. doi: 10.1186/s40164-022-00339-1.
Aberrant DNA methylation (DNAm) is an important epigenetic regulator in various cancers. Pan-cancer DNAm analyses have investigated the potential common mechanisms of DNAm in tumorigenesis. However, these pan-cancer studies focused on adult cancers rather than pediatric cancers, which may have distinct pathology and treatment responses. Here, we performed a pan-cancer analysis of genome-wide DNAm in over 2,000 samples from nine pediatric cancers to elucidate the DNAm landscape of pediatric cancers. We identified 217,586 differentially methylated CpG sites (DMCs) in pediatric cancers, with a tendency toward hypermethylation as opposed to hypomethylation (P = 0.02). Amongst them, 75.65% also presented DNAm alterations in adult cancers. In nine pediatric cancers, we defined 54 shared DMCs (SDMCs), which were also observed in at least one adult cancer type. Furthermore, methylation patterns in SDMCs influenced the transcription of several genes (MEIS1, MIA3, PCDHAC2, SH3BP4, and ATP8B1) involved in well-known cancer-related pathways and cancer hallmarks (FDR < 0.05). Moreover, SDMCs were significantly associated with patient survival, and this association was independent of sex, age, and tumor stage (P < 0.05). Interestingly, SDMCs could affect patient survival not only in the nine pediatric cancers that were used to identify SDMCs but also in other untested pediatric cancers (P < 0.05). Collectively, our data depicts a comprehensive landscape of aberrant DNA methylation in pediatric cancers, which is partly similar to that of adult cancers. We also suggest a potential clinical application of SDMCs as biomarkers for the prognosis of pediatric cancer.
异常DNA甲基化（DNAm）是多种癌症中一种重要的表观遗传调节因子。泛癌DNAm分析已经研究了DNAm在肿瘤发生中的潜在共同机制。然而，这些泛癌研究主要集中在成人癌症而非儿童癌症上，儿童癌症可能具有不同的病理学特征和治疗反应。在此，我们对来自九种儿童癌症的2000多个样本进行了全基因组DNAm的泛癌分析，以阐明儿童癌症的DNAm图谱。我们在儿童癌症中鉴定出217,586个差异甲基化的CpG位点（DMC），与低甲基化相比，呈现出高甲基化的趋势（P = 0.02）。其中，75.65%在成人癌症中也存在DNAm改变。在九种儿童癌症中，我们定义了54个共享DMC（SDMC），这些位点在至少一种成人癌症类型中也被观察到。此外，SDMC中的甲基化模式影响了几个参与著名癌症相关通路和癌症标志的基因（MEIS1、MIA3、PCDHAC2、SH3BP4和ATP8B1）的转录（FDR < 0.05）。此外，SDMC与患者生存显著相关，且这种关联独立于性别、年龄和肿瘤分期（P < 0.05）。有趣的是，SDMC不仅可以影响用于鉴定SDMC的九种儿童癌症患者的生存，还能影响其他未测试的儿童癌症患者的生存（P < 0.05）。总体而言，我们的数据描绘了儿童癌症中异常DNA甲基化的全面图谱，部分与成人癌症相似。我们还提出了SDMC作为儿童癌症预后生物标志物的潜在临床应用。
