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Landscape of Germline and Somatic Mitochondrial DNA Mutations in Pediatric Malignancies

机译:细胞儿科恶性肿瘤和体细胞线粒体DNA突变的景观

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摘要

Little is known about the spectrum of mitochondrial DNA (mtDNA) mutations across pediatric malignancies. In this study, we analyzed matched tumor and normal whole genome sequencing data from 616 pediatric patients with hematopoietic malignancies, solid tumors, and brain tumors. We identified 391 mtDNA mutations in 284 tumors including 45 loss-of-function mutations, which clustered at four statistically significant hotspots in MT-COX3, MT-ND4, and MT-ND5, and at a mutation hotspot in MT-tRNA-MET. A skewed ratio (4.83) of nonsynonymous versus synonymous (dN/dS) mtDNA mutations with high statistical significance was identified on the basis of Monte Carlo simulations in the tumors. In comparison, opposite ratios of 0.44 and 0.93 were observed in 616 matched normal tissues and in 249 blood samples from children without cancer, respectively. mtDNA mutations varied by cancer type and mtDNA haplogroup. Collectively, these results suggest that deleterious mtDNAmutations play a role in the development and progression of pediatric cancers.
机译:关于儿科恶性肿瘤的线粒体DNA(MTDNA)突变的光谱知之甚少。在这项研究中,我们分析了616名儿科患者造血恶性肿瘤,实体肿瘤和脑肿瘤的匹配肿瘤和正常全基因组测序数据。我们在284例肿瘤中鉴定了391个MTDNA突变,其中包括45个功能突变,其在MT-COX3,MT-ND4和MT-ND5中的四个统计学显着的热点聚集,并且在MT-TRNA-MET中的突变热点处。在肿瘤中的蒙特卡罗模拟的基础上,鉴定了具有高统计显着性的非纯类与同义(DN / DS)MTDNA突变的偏差比率(4.83)。相比之下,在616种匹配的正常组织中观察到0.44和0.93的相反比例分别观察到来自没有癌症的儿童的249例血液样本。 MTDNA突变因癌症类型和MTDNA HAPLOGroup而变化。总的来说,这些结果表明,有害的MTDNamutations在儿科癌症的发展和进展中发挥作用。

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