A sequence-based survey of the complex structural organization of tumor genomes.
BACKGROUND
The genomes of many epithelial tumors exhibit extensive chromosomal rearrangements. All classes of genome rearrangements can be identified using end sequencing profiling, which relies on paired-end sequencing of cloned tumor genomes.


RESULTS
In the present study brain, breast, ovary, and prostate tumors, along with three breast cancer cell lines, were surveyed using end sequencing profiling, yielding the largest available collection of sequence-ready tumor genome breakpoints and providing evidence that some rearrangements may be recurrent. Sequencing and fluorescence in situ hybridization confirmed translocations and complex tumor genome structures that include co-amplification and packaging of disparate genomic loci with associated molecular heterogeneity. Comparison of the tumor genomes suggests recurrent rearrangements. Some are likely to be novel structural polymorphisms, whereas others may be bona fide somatic rearrangements. A recurrent fusion transcript in breast tumors and a constitutional fusion transcript resulting from a segmental duplication were identified. Analysis of end sequences for single nucleotide polymorphisms revealed candidate somatic mutations and an elevated rate of novel single nucleotide polymorphisms in an ovarian tumor.


CONCLUSIONS
These results suggest that the genomes of many epithelial tumors may be far more dynamic and complex than was previously appreciated and that genomic fusions, including fusion transcripts and proteins, may be common, possibly yielding tumor-specific biomarkers and therapeutic targets.
Raphael
Benjamin J
BJ
Department of Computer Science & Center for Computational Molecular Biology, Brown University, Waterman Street, Providence, RI 02912-1910, USA. braphael@brown.edu
Volik
Stanislav
S
Yu
Peng
P
Wu
Chunxiao
C
Huang
Guiqing
G
Linardopoulou
Elena V
EV
Trask
Barbara J
BJ
Waldman
Frederic
F
Costello
Joseph
J
Pienta
Kenneth J
KJ
Mills
Gordon B
GB
Bajsarowicz
Krystyna
K
Kobayashi
Yasuko
Y
Sridharan
Shivaranjani
S
Paris
Pamela L
PL
Tao
Quanzhou
Q
Aerni
Sarah J
SJ
Brown
Raymond P
RP
Bashir
Ali
A
Gray
Joe W
JW
Cheng
Jan-Fang
JF
de Jong
Pieter
P
Nefedov
Mikhail
M
Ried
Thomas
T
Padilla-Nash
Hesed M
HM
Collins
Colin C
CC
D002277:Carcinoma / Q000235:genetics*; D045744:Cell Line, Tumor; D002874:Chromosome Mapping; D022202:Chromosomes, Artificial, Bacterial; D053960:DNA Breaks; D015723:Gene Library; D023061:Gene Order; D052138:Genes, Neoplasm; D015894:Genome, Human; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D011995:Recombination, Genetic; D017422:Sequence Analysis, DNA; D014158:Transcription, Genetic