The mutation spectrum revealed by paired genome sequences from a lung cancer patient.
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.
Lee
William
W
Department of Bioinformatics and Computational Biology, Genentech Inc., South San Francisco, California 94080, USA.
Jiang
Zhaoshi
Z
Liu
Jinfeng
J
Haverty
Peter M
PM
Guan
Yinghui
Y
Stinson
Jeremy
J
Yue
Peng
P
Zhang
Yan
Y
Pant
Krishna P
KP
Bhatt
Deepali
D
Ha
Connie
C
Johnson
Stephanie
S
Kennemer
Michael I
MI
Mohan
Sankar
S
Nazarenko
Igor
I
Watanabe
Colin
C
Sparks
Andrew B
AB
Shames
David S
DS
Gentleman
Robert
R
de Sauvage
Frederic J
FJ
Stern
Howard
H
Pandita
Ajay
A
Ballinger
Dennis G
DG
Drmanac
Radoje
R
Modrusan
Zora
Z
Seshagiri
Somasekar
S
Zhang
Zemin
Z
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