Identification of somatically acquired rearrangements in cancer using genome-wide massively parallel paired-end sequencing.
Human cancers often carry many somatically acquired genomic rearrangements, some of which may be implicated in cancer development. However, conventional strategies for characterizing rearrangements are laborious and low-throughput and have low sensitivity or poor resolution. We used massively parallel sequencing to generate sequence reads from both ends of short DNA fragments derived from the genomes of two individuals with lung cancer. By investigating read pairs that did not align correctly with respect to each other on the reference human genome, we characterized 306 germline structural variants and 103 somatic rearrangements to the base-pair level of resolution. The patterns of germline and somatic rearrangement were markedly different. Many somatic rearrangements were from amplicons, although rearrangements outside these regions, notably including tandem duplications, were also observed. Some somatic rearrangements led to abnormal transcripts, including two from internal tandem duplications and two fusion transcripts created by interchromosomal rearrangements. Germline variants were predominantly mediated by retrotransposition, often involving AluY and LINE elements. The results demonstrate the feasibility of systematic, genome-wide characterization of rearrangements in complex human cancer genomes, raising the prospect of a new harvest of genes associated with cancer using this strategy.
Campbell
Peter J
PJ
Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
Stephens
Philip J
PJ
Pleasance
Erin D
ED
O'Meara
Sarah
S
Li
Heng
H
Santarius
Thomas
T
Stebbings
Lucy A
LA
Leroy
Catherine
C
Edkins
Sarah
S
Hardy
Claire
C
Teague
Jon W
JW
Menzies
Andrew
A
Goodhead
Ian
I
Turner
Daniel J
DJ
Clee
Christopher M
CM
Quail
Michael A
MA
Cox
Antony
A
Brown
Clive
C
Durbin
Richard
R
Hurles
Matthew E
ME
Edwards
Paul A W
PA
Bignell
Graham R
GR
Stratton
Michael R
MR
Futreal
P Andrew
PA
D020029:Base Pairing; D002874:Chromosome Mapping; D019295:Computational Biology; D018628:Gene Dosage; D015321:Gene Rearrangement / Q000235:genetics*; D014644:Genetic Variation; D015894:Genome, Human; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012091:Repetitive Sequences, Nucleic Acid; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA
D012333:RNA, Messenger