The mutation spectrum revealed by paired genome sequences from a lung cancer patient View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2010-05

AUTHORS

William Lee, Zhaoshi Jiang, Jinfeng Liu, Peter M. Haverty, Yinghui Guan, Jeremy Stinson, Peng Yue, Yan Zhang, Krishna P. Pant, Deepali Bhatt, Connie Ha, Stephanie Johnson, Michael I. Kennemer, Sankar Mohan, Igor Nazarenko, Colin Watanabe, Andrew B. Sparks, David S. Shames, Robert Gentleman, Frederic J. de Sauvage, Howard Stern, Ajay Pandita, Dennis G. Ballinger, Radoje Drmanac, Zora Modrusan, Somasekar Seshagiri, Zemin Zhang

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. More... »

PAGES

473

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/nature09004

DOI

http://dx.doi.org/10.1038/nature09004

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1042375369

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/20505728


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