Cytogenetically balanced translocations are associated with focal copy number alterations.
Current cytogenetic methods (e.g., G-banding and multicolor chromosomal painting) allow detection of translocation events but lack the resolution to (a) locate the breakpoints precisely at the chromosome band level or (b) discriminate balanced translocations from translocations with copy number alterations not previously reported, or imperfectly balanced translocations. In this study, we demonstrate that cytogenetically balanced translocations are in fact frequently associated with segmental gain or loss of DNA. The recent development of a whole genome tiling path BAC array has enabled tiling resolution analysis of genomic segmental copy number status. Combining tiling resolution BAC array comparative genomic hybridization (array CGH) with G-Banding analysis and multicolor chromosomal painting approaches such as spectral karyotyping (SKY) facilitates high-resolution mapping of genomic alterations associated with imperfectly balanced translocations. Using a refined version of our CGH array we have deduced the copy number status throughout the genomes of three cytogenetically well-characterized prostate cancer cell lines (PC3, DU145, LNCaP) to determine whether translocations are associated with focal gains and losses of DNA. At 78 kb tiling resolution we identified the boundaries of 170, 80, and 34 known and novel copy number alterations (CNA) in these cell line genomes, respectively. Thirty-three of the 36 known translocations (92%, P < 0.001) in DU145 were associated with segmental CNA. Likewise, 80% (P < 0.001) of the known translocations showed association in LNCaP. Although many translocation breakpoints exhibit segmental alteration in PC3, the pattern of chromosomal rearrangements is too complex for use in comprehensive association with CNA boundaries. Our results reveal that imperfectly balanced translocations in tumor genomes are a phenomenon that occurs at frequencies much higher than previously demonstrated.
Watson
Spencer K
SK
Cancer Genetics and Developmental Biology, British Columbia Cancer Research Centre, 675 West 10th Avenue, Vancouver, BC, Canada. swatson@bccrc.ca
deLeeuw
Ronald J
RJ
Horsman
Doug E
DE
Squire
Jeremy A
JA
Lam
Wan L
WL
D045744:Cell Line, Tumor; D022202:Chromosomes, Artificial, Bacterial / Q000235:genetics; D002877:Chromosomes, Human / Q000235:genetics; D003582:Cytogenetics; D004273:DNA, Neoplasm / Q000235:genetics; D018628:Gene Dosage; D020869:Gene Expression Profiling; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D011003:Ploidies; D011471:Prostatic Neoplasms / Q000235:genetics; D014178:Translocation, Genetic
D004273:DNA, Neoplasm