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科学家揭示癌症中RNA改变的基因组基础
2020-02-12 13:11

瑞士苏黎世联邦理工学院Gunnar Rätsch、美国加州大学圣克鲁斯分校Angela N. Brooks和英国欧洲分子生物学实验室Alvis Brazma合作探究了癌症中RNA改变的基因组基础。这一研究成果2020年2月5日在线发表在国际学术期刊《自然》上。

研究人员介绍了迄今为止最全面的癌症相关基因改变图谱,该图谱分析了来自国际癌症基因组联合会(ICGC)全基因组泛癌分析(PCAWG)联合会和《癌症基因组图谱》(TCGA)的1,188个供体肿瘤样本的转录组。使用匹配的全基因组测序数据,研究人员将几类RNA改变与种系和体细胞DNA改变相关联,并确定了可能的遗传机制。体细胞基因拷贝数变化是总基因和等位基因特异性表达变化的主要驱动力。研究人员发现649个体细胞单核苷酸突变与顺式表达相关联,其中68.4%与该基因侧翼非编码区有关。研究人员还发现1,900个与体细胞突变相关的剪接改变,包括在Alu元件附近的内含子内剪接形成外显子。此外,有82%的基因融合与结构变异有关,包括75种新的“桥接”融合,即第三个基因组位置桥接了两个基因。研究人员观察到转录组改变特征在癌症类型之间是不同的,并且与DNA突变特征变化相关。在基因组背景下,这种RNA改变图谱为鉴定与癌症功能相关的基因和机制提供了丰富的资源。

据悉,转录水平的改变通常是由癌症基因组的体细胞变化引起的。在癌症细胞中存在各种形式的RNA改变,包括过表达、剪接改变和基因融合。然而,由于患者和肿瘤类型之间的异质性,以及对相对较小的患者样本进行转录组和全基因组测序分析,所以很难将这些归因于潜在的基因组变化。

附:英文原文

Title: Genomic basis for RNA alterations in cancer

Author: Claudia Calabrese, Natalie R. Davidson, Deniz Demirciolu, Nuno A. Fonseca, Yao He, Andr Kahles, Kjong-Van Lehmann, Fenglin Liu, Yuichi Shiraishi, Cameron M. Soulette, Lara Urban, Liliana Greger, Siliang Li, Dongbing Liu, Marc D. Perry, Qian Xiang, Fan Zhang, Junjun Zhang, Peter Bailey, Serap Erkek, Katherine A. Hoadley, Yong Hou, Matthew R. Huska, Helena Kilpinen, Jan O. Korbel, Maximillian G. Marin, Julia Markowski, Tannistha Nandi, Qiang Pan-Hammarstrm, Chandra Sekhar Pedamallu, Reiner Siebert, Stefan G. Stark, Hong Su, Patrick Tan, Sebastian M. Waszak, Christina Yung, Shida Zhu, Philip Awadalla, Chad J. Creighton, Matthew Meyerson, B. F. Francis Ouellette, Kui Wu, Huanming Yang, Alvis Brazma, Angela N. Brooks, Jonathan Gke, Gunnar Rtsch, Roland F. Schwarz, Oliver Stegle, Zemin Zhang

Issue&Volume: 2020-02-05

Abstract: Transcript alterations often result from somatic changes in cancer genomes1. Various forms of RNA alterations have been described in cancer, including overexpression2, altered splicing3 and gene fusions4; however, it is difficult to attribute these to underlying genomic changes owing to heterogeneity among patients and tumour types, and the relatively small cohorts of patients for whom samples have been analysed by both transcriptome and whole-genome sequencing. Here we present, to our knowledge, the most comprehensive catalogue of cancer-associated gene alterations to date, obtained by characterizing tumour transcriptomes from 1,188 donors of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA)5. Using matched whole-genome sequencing data, we associated several categories of RNA alterations with germline and somatic DNA alterations, and identified probable genetic mechanisms. Somatic copy-number alterations were the major drivers of variations in total gene and allele-specific expression. We identified 649 associations of somatic single-nucleotide variants with gene expression in cis, of which 68.4% involved associations with flanking non-coding regions of the gene. We found 1,900 splicing alterations associated with somatic mutations, including the formation of exons within introns in proximity to Alu elements. In addition, 82% of gene fusions were associated with structural variants, including 75 of a new class, termed ‘bridged’ fusions, in which a third genomic location bridges two genes. We observed transcriptomic alteration signatures that differ between cancer types and have associations with variations in DNA mutational signatures. This compendium of RNA alterations in the genomic context provides a rich resource for identifying genes and mechanisms that are functionally implicated in cancer.

DOI: 10.1038/s41586-020-1970-0

Source: https://www.nature.com/articles/s41586-020-1970-0

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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