Chromosomal breakpoints in primary colon cancer cluster at sites of structural variants in the genome.
Genomic aberrations on chromosome 8 are common in colon cancer, and are associated with lymph node and distant metastases as well as with disease susceptibility. This prompted us to generate a high-resolution map of genomic imbalances of chromosome 8 in 51 primary colon carcinomas using a custom-designed genomic array consisting of a tiling path of BAC clones. This analysis confirmed the dominant role of this chromosome. Unexpectedly, the position of the breakpoints suggested colocalization with structural variants in the human genome. In order to map these sites with increased resolution and to extend the analysis to the entire genome, we analyzed a subset of these tumors (n = 32) by comparative genomic hybridization on a 185K oligonucleotide array platform. Our comprehensive map of the colon cancer genome confirmed recurrent and specific low-level copy number changes of chromosomes 7, 8, 13, 18, and 20, and unveiled additional, novel sites of genomic imbalances including amplification of a histone gene cluster on chromosome 6p21.1-21.33 and deletions on chromosome 4q34-35. The systematic comparison of segments of copy number change with gene expression profiles showed that genomic imbalances directly affect average expression levels. Strikingly, we observed a significant association of chromosomal breakpoints with structural variants in the human genome: 41% of all copy number changes occurred at sites of such copy number variants (P < 2.2e(-16)). Such an association has not been previously described and reveals a yet underappreciated plasticity of the colon cancer genome; it also points to potential mechanisms for the induction of chromosomal breakage in cancer cells.
Camps
Jordi
J
Genetics Branch, Center for Cancer Research, National Cancer Institute/NIH, Bethesda, MD 20892, USA.
Grade
Marian
M
Nguyen
Quang Tri
QT
Hörmann
Patrick
P
Becker
Sandra
S
Hummon
Amanda B
AB
Rodriguez
Virginia
V
Chandrasekharappa
Settara
S
Chen
Yidong
Y
Difilippantonio
Michael J
MJ
Becker
Heinz
H
Ghadimi
B Michael
BM
Ried
Thomas
T
D002869:Chromosome Aberrations; D002874:Chromosome Mapping; D002875:Chromosomes / Q000648:ultrastructure*; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016678:Genome; D015894:Genome, Human; D006657:Histones / Q000378:metabolism; D006801:Humans; D008297:Male; D005810:Multigene Family; D020411:Oligonucleotide Array Sequence Analysis; D009841:Oligonucleotides / Q000737:chemistry; D011110:Polymorphism, Genetic
D006657:Histones; D009841:Oligonucleotides