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首页> 外文期刊>PLoS Genetics >Ribosomal DNA copy number amplification and loss in human cancers is linked to tumor genetic context, nucleolus activity, and proliferation
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Ribosomal DNA copy number amplification and loss in human cancers is linked to tumor genetic context, nucleolus activity, and proliferation

机译：人癌中的核糖体DNA拷贝数扩增和丢失与肿瘤的遗传背景，核仁活性和增殖有关

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Ribosomal RNAs (rRNAs) are transcribed from two multicopy DNA arrays: the 5S ribosomal DNA (rDNA) array residing in a single human autosome and the 45S rDNA array residing in five human autosomes. The arrays are among the most variable segments of the genome, exhibit concerted copy number variation (cCNV), encode essential components of the ribosome, and modulate global gene expression. Here we combined whole genome data from >700 tumors and paired normal tissues to provide a portrait of rDNA variation in human tissues and cancers of diverse mutational signatures, including stomach and lung adenocarcinomas, ovarian cancers, and others of the TCGA panel. We show that cancers undergo coupled 5S rDNA array expansion and 45S rDNA loss that is accompanied by increased estimates of proliferation rate and nucleolar activity. These somatic changes in rDNA CN occur in a background of over 10-fold naturally occurring rDNA CN variation across individuals and cCNV of 5S-45S arrays in some but not all tissues. Analysis of genetic context revealed associations between cancer rDNA CN amplification or loss and the presence of specific somatic alterations, including somatic SNPs and copy number gain/losses in protein coding genes across the cancer genome. For instance, somatic inactivation of the tumor suppressor gene TP53 emerged with a strong association with coupled 5S expansion / 45S loss in several cancers. Our results uncover frequent and contrasting changes in the 5S and 45S rDNA along rapidly proliferating cell lineages with high nucleolar activity. We suggest that 5S rDNA amplification facilitates increased proliferation, nucleolar activity, and ribosomal synthesis in cancer, whereas 45S rDNA loss emerges as a byproduct of transcription-replication conflict in rapidly replicating tumor cells. The observations raise the prospects of using the rDNA arrays as re-emerging targets for the design of novel strategies in cancer therapy.
机译：核糖体RNA（rRNA）从两个多拷贝DNA阵列转录而成：驻留在单个人常染色体中的5S核糖体DNA（rDNA）阵列和驻留在五个人常染色体中的45S rDNA阵列。该阵列是基因组中可变性最强的片段，具有一致的拷贝数变异（cCNV），编码核糖体的基本成分并调节整体基因表达。在这里，我们结合了来自> 700多个肿瘤和配对的正常组织的全基因组数据，以提供人组织和具有多种突变特征的癌症（包括胃和肺腺癌，卵巢癌以及TCGA专家组）中的rDNA变异的肖像。我们显示癌症经历耦合的5S rDNA阵列扩展和45S rDNA损失，伴随着增殖率和核仁活性的增加的估计。 rDNA CN的这些体细胞变化发生在个体和某些组织而非全部组织中5S-45S阵列的cCNV超过10倍自然发生的rDNA CN变异的背景下。遗传背景分析揭示了癌症rDNA CN扩增或丢失与特定体细胞变化（包括体SNP和整个癌症基因组中蛋白质编码基因的拷贝数增/减）之间的关联。例如，在几种癌症中，抑癌基因TP53的体细胞失活与5S扩展/ 45S缺失相关。我们的研究结果揭示了沿具有高核仁活性的快速增殖细胞谱系，5S和45S rDNA频繁且形成对比的变化。我们建议5S rDNA扩增促进癌症中增殖，核仁活性和核糖体合成的增加，而45S rDNA丢失作为转录复制冲突的副产物出现在快速复制的肿瘤细胞中。观察结果提出了使用rDNA阵列作为重新出现的靶标来设计癌症治疗新策略的前景。

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