Integrated genomic analysis of mitochondrial RNA processing in human cancers.
Integrated genomic analysis of mitochondrial RNA processing in human cancers.
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DOI：
10.1186/s13073-017-0426-0
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发表时间：
2017-04-18
期刊：
影响因子：
12.3
通讯作者：
Hodgkinson A
中科院分区：
文献类型：
--
作者：
Idaghdour Y;Hodgkinson A
线粒体基因组转录为含有多个基因的RNA的连续多顺反子。因此，转录后事件对于基因表达的调节以及因此线粒体功能的所有方面都是至关重要的。一个特别重要的过程是不同线粒体tRNA的第九位的m1A/m1 G RNA甲基化，其允许线粒体mRNA的有效加工和蛋白质翻译，并且参与这些过程的基因的失调与线粒体功能的改变有关。虽然线粒体在癌症中起着关键作用，但线粒体RNA加工在肿瘤发生中的地位尚不清楚。我们使用来自12种不同癌症类型的1226个样本的RNA测序和基因分型数据的综合基因组分析来测量和评估线粒体RNA加工。我们专注于正常和肿瘤样本中线粒体tRNA的m1A和m1 G RNA甲基化水平，并使用监督和非监督统计分析来比较这些修饰与患者全基因组基因型，核基因表达和生存结果的水平。我们在所有癌症的肿瘤组织中发现线粒体tRNA中m1A和m1 G RNA甲基化水平的显着变化。RNA加工途径与正常组织中的甲基化水平密切相关（P = 3.27 × 10−31），但这些相关性在肿瘤中丢失。此外，我们报告了18种基因与疾病状态的相互作用，其中改变的RNA甲基化水平发生在以基因型为条件的癌症状态下，涉及与线粒体功能或癌症相关的基因（例如，CACNA 2D 2，LMO 2和FLT 3），并表明核遗传变异可以潜在地调节个体在癌症状态下维持线粒体RNA加工速率不变的能力。最后，我们报告了肿瘤中甲基化水平变化的幅度与患者生存结局之间的显著相关性。我们报告了在研究的所有癌症类型中正常组织和肿瘤组织之间线粒体RNA加工的广泛变化，并表明这些变化可能受患者基因型的调节，并可能影响患者的生存结局。这些结果突出了线粒体RNA加工改变的潜在临床相关性，并为这些事件在癌症中的重要性和复杂性提供了广泛的新见解。本文的在线版本（doi：10.1186/s13073-017-0426-0）包含补充材料，可供授权用户使用。
The mitochondrial genome is transcribed as continuous polycistrons of RNA containing multiple genes. As a consequence, post-transcriptional events are critical for the regulation of gene expression and therefore all aspects of mitochondrial function. One particularly important process is the m1A/m1G RNA methylation of the ninth position of different mitochondrial tRNAs, which allows efficient processing of mitochondrial mRNAs and protein translation, and de-regulation of genes involved in these processes has been associated with altered mitochondrial function. Although mitochondria play a key role in cancer, the status of mitochondrial RNA processing in tumorigenesis is unknown. We measure and assess mitochondrial RNA processing using integrated genomic analysis of RNA sequencing and genotyping data from 1226 samples across 12 different cancer types. We focus on the levels of m1A and m1G RNA methylation in mitochondrial tRNAs in normal and tumor samples and use supervised and unsupervised statistical analysis to compare the levels of these modifications to patient whole genome genotypes, nuclear gene expression, and survival outcomes. We find significant changes to m1A and m1G RNA methylation levels in mitochondrial tRNAs in tumor tissues across all cancers. Pathways of RNA processing are strongly associated with methylation levels in normal tissues (P = 3.27 × 10−31), yet these associations are lost in tumors. Furthermore, we report 18 gene-by-disease-state interactions where altered RNA methylation levels occur under cancer status conditional on genotype, implicating genes associated with mitochondrial function or cancer (e.g., CACNA2D2, LMO2, and FLT3) and suggesting that nuclear genetic variation can potentially modulate an individual’s ability to maintain unaltered rates of mitochondrial RNA processing under cancer status. Finally, we report a significant association between the magnitude of methylation level changes in tumors and patient survival outcomes. We report widespread variation of mitochondrial RNA processing between normal and tumor tissues across all cancer types investigated and show that these alterations are likely modulated by patient genotype and may impact patient survival outcomes. These results highlight the potential clinical relevance of altered mitochondrial RNA processing and provide broad new insights into the importance and complexity of these events in cancer. The online version of this article (doi:10.1186/s13073-017-0426-0) contains supplementary material, which is available to authorized users.