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  • The mutation spectrum revea...
    LEE, William; ZHAOSHI JIANG; HA, Connie; JOHNSON, Stephanie; KENNEMER, Michael I; MOHAN, Sankar; NAZARENKO, Igor; WATANABE, Colin; SPARKS, Andrew B; SHAMES, David S; GENTLEMAN, Robert; DE SAUVAGE, Frederic J; JINFENG LIU; STERN, Howard; PANDITA, Ajay; BALLINGER, Dennis G; DRMANAC, Radoje; MODRUSAN, Zora; SESHAGIRI, Somasekar; ZEMIN ZHANG; HAVERTY, Peter M; YINGHUI GUAN; STINSON, Jeremy; PENG YUE; YAN ZHANG; PANT, Krishna P; BHATT, Deepali

    Nature (London), 05/2010, Letnik: 465, Številka: 7297
    Journal Article

    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.