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配对肺癌患者基因组序列揭示的突变谱。

The mutation spectrum revealed by paired genome sequences from a lung cancer patient.

机构信息

Department of Bioinformatics and Computational Biology, Genentech Inc., South San Francisco, California 94080, USA.

出版信息

Nature. 2010 May 27;465(7297):473-7. doi: 10.1038/nature09004.


DOI:10.1038/nature09004
PMID:20505728
Abstract

Lung cancer is the leading cause of cancer-related mortality worldwide, with non-small-cell lung carcinomas in smokers being the predominant form of the disease. Although previous studies have identified important common somatic mutations in lung cancers, they have primarily focused on a limited set of genes and have thus provided a constrained view of the mutational spectrum. Recent cancer sequencing efforts have used next-generation sequencing technologies to provide a genome-wide view of mutations in leukaemia, breast cancer and cancer cell lines. Here we present the complete sequences of a primary lung tumour (60x coverage) and adjacent normal tissue (46x). Comparing the two genomes, we identify a wide variety of somatic variations, including >50,000 high-confidence single nucleotide variants. We validated 530 somatic single nucleotide variants in this tumour, including one in the KRAS proto-oncogene and 391 others in coding regions, as well as 43 large-scale structural variations. These constitute a large set of new somatic mutations and yield an estimated 17.7 per megabase genome-wide somatic mutation rate. Notably, we observe a distinct pattern of selection against mutations within expressed genes compared to non-expressed genes and in promoter regions up to 5 kilobases upstream of all protein-coding genes. Furthermore, we observe a higher rate of amino acid-changing mutations in kinase genes. We present a comprehensive view of somatic alterations in a single lung tumour, and provide the first evidence, to our knowledge, of distinct selective pressures present within the tumour environment.

摘要

肺癌是全球癌症相关死亡的主要原因,吸烟者的非小细胞肺癌是该病的主要形式。尽管先前的研究已经确定了肺癌中重要的常见体细胞突变,但它们主要集中在有限数量的基因上,因此提供了对突变谱的有限看法。最近的癌症测序工作使用下一代测序技术提供了白血病、乳腺癌和癌细胞系中突变的全基因组视图。在这里,我们展示了一个原发性肺肿瘤(60x 覆盖)和相邻正常组织(46x)的完整序列。比较这两个基因组,我们确定了各种各样的体细胞变异,包括>50000 个高置信度单核苷酸变异。我们在这个肿瘤中验证了 530 个体细胞单核苷酸变异,包括 KRAS 原癌基因中的一个和编码区域中的 391 个,以及 43 个大规模结构变异。这些构成了一大组新的体细胞突变,并产生了估计为每百万碱基基因组 17.7 的全基因组体细胞突变率。值得注意的是,我们观察到与表达基因相比,非表达基因和所有蛋白质编码基因上游达 5 千碱基的启动子区域内的突变受到明显的选择压力。此外,我们观察到激酶基因中的氨基酸改变突变率更高。我们展示了单个肺肿瘤中体细胞改变的综合视图,并提供了我们所知的肿瘤环境中存在明显选择压力的第一个证据。

相似文献

[1]
The mutation spectrum revealed by paired genome sequences from a lung cancer patient.

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[2]
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本文引用的文献

[1]
A small-cell lung cancer genome with complex signatures of tobacco exposure.

Nature. 2009-12-16

[2]
A comprehensive catalogue of somatic mutations from a human cancer genome.

Nature. 2009-12-16

[3]
Human genome sequencing using unchained base reads on self-assembling DNA nanoarrays.

Science. 2009-11-5

[4]
Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution.

Nature. 2009-10-8

[5]
Exon array profiling detects EML4-ALK fusion in breast, colorectal, and non-small cell lung cancers.

Mol Cancer Res. 2009-9-8

[6]
Recurring mutations found by sequencing an acute myeloid leukemia genome.

N Engl J Med. 2009-9-10

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Circos: an information aesthetic for comparative genomics.

Genome Res. 2009-9

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Nature. 2009-4-9

[9]
The Human Gene Mutation Database: 2008 update.

Genome Med. 2009-1-22

[10]
DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome.

Nature. 2008-11-6

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