Ribosomal DNA copy number amplification and loss in human cancers is linked to tumor genetic context, nucleolus activity, and proliferation.
Ribosomal DNA copy number amplification and loss in human cancers is linked to tumor genetic context, nucleolus activity, and proliferation.
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DOI：
10.1371/journal.pgen.1006994
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发表时间：
2017-09
期刊：
影响因子：
4.5
通讯作者：
Lemos B
中科院分区：
文献类型：
--
作者：
Wang M;Lemos B
核糖体RNA（rRNA）是从两个多拷贝DNA阵列转录的：5S核糖体DNA（rDNA）阵列驻留在一个单一的人类常染色体和45 S rDNA阵列驻留在五个人类常染色体。该阵列是基因组中最可变的片段之一，表现出协同拷贝数变异（cCNV），编码核糖体的基本组分，并调节全局基因表达。在这里，我们结合了来自>700个肿瘤和配对正常组织的全基因组数据，以提供人类组织和具有不同突变特征的癌症（包括胃癌和肺腺癌、卵巢癌和TCGA小组的其他癌症）中rDNA变异的画像。我们发现，癌症经历耦合5S rDNA阵列扩展和45 S rDNA的损失，伴随着增殖率和核仁活性的估计增加。rDNA CN的这些体细胞变化发生在个体间超过10倍天然存在的rDNA CN变异和某些但不是所有组织中5S-45 S阵列的cCNV的背景下。遗传背景的分析揭示了癌症rDNA CN扩增或丢失与特定体细胞改变的存在之间的关联，包括体细胞SNP和整个癌症基因组中蛋白质编码基因的拷贝数增加/丢失。例如，在几种癌症中，肿瘤抑制基因TP 53的体细胞失活与5S扩增/45 S丢失的耦合密切相关。我们的研究结果揭示了5S和45 S rDNA沿着快速增殖的细胞系具有高核仁活性的频繁和对比的变化。我们认为，5S rDNA扩增有利于增加增殖，核仁活性，核糖体合成的癌症，而45 S rDNA的损失出现作为一个副产品的转录复制冲突在快速复制的肿瘤细胞。这些观察提高了使用rDNA阵列作为重新出现的癌症治疗新策略设计的目标的前景。45 S和5S核糖体DNA（rDNA）阵列包含数百个rDNA拷贝，在人群中的个体之间具有很大的差异。虽然物理上不连锁，但阵列也表现出跨个体基因型的联合变异。然而，这种拷贝数（CN）的共变异是否在所有组织中普遍观察到尚不清楚。rDNA CN是否可能在组织和癌症谱系中变化也仍然未知。在这里，我们发现，大多数癌症经历耦合5S rDNA阵列扩增和45 S rDNA的损失，并协调5S-45 S CN的变化，在一些，但不是所有的组织。耦合的5S扩增和45 S丢失与某些体细胞遗传改变的存在以及癌细胞增殖率和核仁活性的估计增加有关。我们的研究揭示了不同组织来源的癌症中rDNA CN的频繁和对比变化，并与肿瘤抑制因子和癌基因的不同突变背景相关。这些观察提高了使用rDNA阵列作为癌症治疗新策略中重新出现的靶点的前景。
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. The 45S and 5S ribosomal DNA (rDNA) arrays contain hundreds of rDNA copies, with substantial variability across individuals in human populations. Although physically unlinked, the arrays also exhibit joint variation across individual genotypes. However, whether this co-variation in copy number (CN) is universally observed across all tissues is unknown. It also remains unknown if rDNA CN might vary across tissues and in cancer lineages. Here we showed that most cancers undergo coupled 5S rDNA array amplification and 45S rDNA loss, and concerted 5S-45S CN variation in some but not all tissues. The coupled 5S amplification and 45S loss is associated with the presence of certain somatic genetic alterations, as well as increased estimates of cancerous cell proliferation rate and nucleolar activity. Our research uncovers frequent and contrasting changes in rDNA CN in cancers of diverse tissue origin and associated with diverse mutational contexts of tumor suppressors and oncogenes. The observations raise the prospects of using the rDNA arrays as re-emerging targets in novel strategies for cancer therapy.
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影响因子：
7.7
作者：
Ju YS;Alexandrov LB;Gerstung M;Martincorena I;Nik-Zainal S;Ramakrishna M;Davies HR;Papaemmanuil E;Gundem G;Shlien A;Bolli N;Behjati S;Tarpey PS;Nangalia J;Massie CE;Butler AP;Teague JW;Vassiliou GS;Green AR;Du MQ;Unnikrishnan A;Pimanda JE;Teh BT;Munshi N;Greaves M;Vyas P;El-Naggar AK;Santarius T;Collins VP;Grundy R;Taylor JA;Hayes DN;Malkin D;ICGC Breast Cancer Group;ICGC Chronic Myeloid Disorders Group;ICGC Prostate Cancer Group;Foster CS;Warren AY;Whitaker HC;Brewer D;Eeles R;Cooper C;Neal D;Visakorpi T;Isaacs WB;Bova GS;Flanagan AM;Futreal PA;Lynch AG;Chinnery PF;McDermott U;Stratton MR;Campbell PJ
通讯作者：
Campbell PJ
影响因子：
4.9
作者：
Bao W;Kojima KK;Kohany O
通讯作者：
Kohany O
DOI：
10.4161/nucl.32235
发表时间：
2014-09
期刊：
Nucleus (Austin, Tex.)
影响因子：
--
作者：
James A;Wang Y;Raje H;Rosby R;DiMario P
通讯作者：
DiMario P
影响因子：
8
作者：
Hannan, KM;Hannan, RD;Rothblum, LI
通讯作者：
Rothblum, LI
影响因子：
8
作者：
Hannan, KM;Kennedy, BK;Rothblum, LI
通讯作者：
Rothblum, LI