Nature：与肺癌相关的基因突变
导读：完整基因组测序已为包括肺癌在内的若干种癌症类型的突变谱提供了线索。
最新测序技术意味着，现在有可能从全基因组范围内来观察突变差异，而且现在研究人员对肺癌已经做到了这一点，并对一种原发性肺部肿瘤（一种腺癌，来自一名男子，他15年来每天平均吸烟25支）和相邻正常组织的完整序列进行了比较。
比较结果显示了超过5万个“点突变”，其中530个得到确认，它们当中392个在编码区域，包括以前已知的变异，如KRAS“原致癌基因”突变和放大。这些数据表明，遗传上复杂的肿瘤可能包含很多部分冗余的突变，而且要识别复发性致癌“驱动突变”（driver mutation），将需要对很多尚未测序的样本进行测序。 （生物谷Bioon.com）
生物谷推荐原文出处：
Nature doi:10.1038/nature09004
The mutation spectrum revealed by paired genome sequences from a lung cancer patient
William Lee1, Zhaoshi Jiang1, Jinfeng Liu1, Peter M. Haverty1, Yinghui Guan2, Jeremy Stinson2, Peng Yue1, Yan Zhang1, Krishna P. Pant3, Deepali Bhatt2, Connie Ha2, Stephanie Johnson4, Michael I. Kennemer3, Sankar Mohan5, Igor Nazarenko3, Colin Watanabe1, Andrew B. Sparks3, David S. Shames5, Robert Gentleman1, Frederic J. de Sauvage2, Howard Stern4, Ajay Pandita5, Dennis G. Ballinger3, Radoje Drmanac3, Zora Modrusan2, Somasekar Seshagiri2 & Zemin Zhang1
1Department of Bioinformatics and Computational Biology, Genentech Inc., South San Francisco, California 94080, USA
2Department of Molecular Biology, Genentech Inc., South San Francisco, California 94080, USA
3Complete Genomics Inc., Mountain View, California 94043, USA
4Department of Pathology, Genentech Inc., South San Francisco, California 94080, USA
5Department of Oncology Diagnostics, Genentech Inc., South San Francisco, California 94080, USA
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 disease1, 2. 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 spectrum3, 4, 5, 6, 7, 8. 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 lines9, 10, 11, 12, 13. Here we present the complete sequences of a primary lung tumour (60× coverage) and adjacent normal tissue (46×). 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.
比较结果显示了超过5万个“点突变”，其中530个得到确认，它们当中392个在编码区域，包括以前已知的变异，如KRAS“原致癌基因”突变和放大。这些数据表明，遗传上复杂的肿瘤可能包含很多部分冗余的突变，而且要识别复发性致癌“驱动突变”（driver mutation），将需要对很多尚未测序的样本进行测序。 （生物谷Bioon.com）
生物谷推荐原文出处：
Nature doi:10.1038/nature09004
The mutation spectrum revealed by paired genome sequences from a lung cancer patient
William Lee1, Zhaoshi Jiang1, Jinfeng Liu1, Peter M. Haverty1, Yinghui Guan2, Jeremy Stinson2, Peng Yue1, Yan Zhang1, Krishna P. Pant3, Deepali Bhatt2, Connie Ha2, Stephanie Johnson4, Michael I. Kennemer3, Sankar Mohan5, Igor Nazarenko3, Colin Watanabe1, Andrew B. Sparks3, David S. Shames5, Robert Gentleman1, Frederic J. de Sauvage2, Howard Stern4, Ajay Pandita5, Dennis G. Ballinger3, Radoje Drmanac3, Zora Modrusan2, Somasekar Seshagiri2 & Zemin Zhang1
1Department of Bioinformatics and Computational Biology, Genentech Inc., South San Francisco, California 94080, USA
2Department of Molecular Biology, Genentech Inc., South San Francisco, California 94080, USA
3Complete Genomics Inc., Mountain View, California 94043, USA
4Department of Pathology, Genentech Inc., South San Francisco, California 94080, USA
5Department of Oncology Diagnostics, Genentech Inc., South San Francisco, California 94080, USA
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 disease1, 2. 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 spectrum3, 4, 5, 6, 7, 8. 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 lines9, 10, 11, 12, 13. Here we present the complete sequences of a primary lung tumour (60× coverage) and adjacent normal tissue (46×). 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.
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