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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We thank T. Wu for critical reading of manuscript, C. Santos for sample handling, M. Vasser and the DNA Synthesis Group for oligonucleotide synthesis, J. Turcotte and G. Cavet for coordination, G. Nilsen for data submission, J. Fitzgerald and A. Baucom for data storage, J. Lee for laboratory support, A. Bruce for graphical assistance, and T. Bhangale, S. Jhunhunwala and A. Halpern for discussion.
Authors are employees of either Genentech Inc. or Complete Genomics Inc. Employees of Complete Genomics have stock options in the company.
This file contains Supplementary Sections S1-S10, Supplementary References, legends for Supplementary Tables 1-7 and Supplementary Figures 1-17 with legends. (PDF 4981 kb)
This file contains Supplementary Tables 1 – 7, including column descriptions. See Supplementary Information file for legends. (XLS 11059 kb)
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Lee, W., Jiang, Z., Liu, J. et al. The mutation spectrum revealed by paired genome sequences from a lung cancer patient. Nature 465, 473–477 (2010). https://xs.scihub.ltd/https://doi.org/10.1038/nature09004
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