完整基因組測序已為包括肺癌在內(nèi)的若干種癌癥類型的突變譜提供了線索,。最新測序技術(shù)意味著,，現(xiàn)在有可能從全基因組范圍內(nèi)來觀察突變差異，而且現(xiàn)在研究人員對肺癌已經(jīng)做到了這一點(diǎn)，并對一種原發(fā)性肺部腫瘤（一種腺癌，來自一名男子,，他15年來每天平均吸煙25支）和相鄰正常組織的完整序列進(jìn)行了比較。
比較結(jié)果顯示了超過5萬個(gè)“點(diǎn)突變”,，其中530個(gè)得到確認(rèn),，它們當(dāng)中392個(gè)在編碼區(qū)域，包括以前已知的變異,，如KRAS“原致癌基因”突變和放大,。這些數(shù)據(jù)表明，遺傳上復(fù)雜的腫瘤可能包含很多部分冗余的突變,，而且要識(shí)別復(fù)發(fā)性致癌“驅(qū)動(dòng)突變”（driver mutation）,，將需要對很多尚未測序的樣本進(jìn)行測序。 （生物谷Bioon.com）
生物谷推薦原文出處：
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.
