title: The mutation spectrum revealed by paired genome sequences from a lung cancer patient.
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.
authors.affiliation: Department of Bioinformatics and Computational Biology, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: William
authors.initials: W
authors.lastname: Lee
authors.forename: Zhaoshi
authors.initials: Z
authors.lastname: Jiang
authors.forename: Jinfeng
authors.initials: J
authors.lastname: Liu
authors.forename: Peter M
authors.initials: PM
authors.lastname: Haverty
authors.forename: Yinghui
authors.initials: Y
authors.lastname: Guan
authors.forename: Jeremy
authors.initials: J
authors.lastname: Stinson
authors.forename: Peng
authors.initials: P
authors.lastname: Yue
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Krishna P
authors.initials: KP
authors.lastname: Pant
authors.forename: Deepali
authors.initials: D
authors.lastname: Bhatt
authors.forename: Connie
authors.initials: C
authors.lastname: Ha
authors.forename: Stephanie
authors.initials: S
authors.lastname: Johnson
authors.forename: Michael I
authors.initials: MI
authors.lastname: Kennemer
authors.forename: Sankar
authors.initials: S
authors.lastname: Mohan
authors.forename: Igor
authors.initials: I
authors.lastname: Nazarenko
authors.forename: Colin
authors.initials: C
authors.lastname: Watanabe
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Sparks
authors.forename: David S
authors.initials: DS
authors.lastname: Shames
authors.forename: Robert
authors.initials: R
authors.lastname: Gentleman
authors.forename: Frederic J
authors.initials: FJ
authors.lastname: de Sauvage
authors.forename: Howard
authors.initials: H
authors.lastname: Stern
authors.forename: Ajay
authors.initials: A
authors.lastname: Pandita
authors.forename: Dennis G
authors.initials: DG
authors.lastname: Ballinger
authors.forename: Radoje
authors.initials: R
authors.lastname: Drmanac
authors.forename: Zora
authors.initials: Z
authors.lastname: Modrusan
authors.forename: Somasekar
authors.initials: S
authors.lastname: Seshagiri
authors.forename: Zemin
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics*; D004252:DNA Mutational Analysis; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D017354:Point Mutation / Q000235:genetics*; D000090063:Proto-Oncogene Mas; D012641:Selection, Genetic / Q000235:genetics