Combined Array-Comparative Genomic Hybridization and Single-Nucleotide Polymorphism-Loss of Heterozygosity Analysis Reveals Complex Changes and Multiple Forms of Chromosomal Instability in Colorectal Cancers

Abstract

Cancers with chromosomal instability (CIN) are held to be aneuploid/polyploid with multiple large-scale gains/deletions, but the processes underlying CIN are unclear and different types of CIN might exist. We investigated colorectal cancer cell lines using array-comparative genomic hybridization (CGH) for copy number changes and single-copy number polymorphism (SNP) microarrays for allelic loss (LOH). Many arraybased CGH changes were not found by LOH because they did not cause true reduction-to-homozygosity. Conversely, many regions of SNP-LOH occurred in the absence of copy number change, comprising an average per cell line of 2 chromosomes with complete LOH; 1-2 terminal regions of LOH (mitotic recombination); and 1 interstitial region of LOH. SNP-LOH detected many novel changes, representing possible locations of uncharacterized tumor suppressor loci. Microsatellite unstable (MSI+) lines infrequently showed gains/deletions or whole-chromosome LOH, but their near-diploid karyotypes concealed mitotic recombination frequencies similar to those of MSIÀ lines. We analyzed p53 and chromosome 18q (SMAD4) in detail, including mutation screening. Almost all MSIÀ lines showed LOH and/or deletion of p53 and 18q; some near-triploid lines had acquired three independent changes at these loci. We found consistent results in primary colorectal cancers. Overall, the distributions of mitotic recombination and whole-chromosome LOH in the MSIÀ cell lines differed significantly from random, with some lines having much higher than expected levels of these changes. Moreover, lines with more LOH changes had significantly fewer copy number changes. These data suggest that CIN is not synonymous with copy number change and some cancers have a specific tendency to whole-chromosome deletion and regain or to mitotic recombination. (Cancer Res 2006; 66(7): 3471-9)

Frequent genomic loss at chr16p13.2 is associated with poor prognosis in colorectal cancer

“…CNAs at the chr16p loci have generally not been reported in previous copy number studies of colorectal neoplasia, 11,18,23,[26][27][28][29][30] maybe because the region is located close to the p-terminus where it traditionally have been difficult to identify CNAs using conventional CGH. 31 Although a few studies have reported on losses of the short arm of chr16 in CRC, this has not received much attention.…”

Identification of chromosomal aberrations associated with disease progression and a novel 3q13.31 deletion involving LSAMP gene in osteosarcoma

“…with disease progression and a novel 3q13.31 deletion involving LSAMP gene in osteosarcoma been applied for studies of chromosomal aberrations in cancer (11)(12)(13)(14)(15)(16)(17)(18)(19). SNP arrays detect DNA copy number (CN) changes and cancer-specific loss of heterozygosity (LOH) in a genomewide fashion.…”

Genome-wide detection of recurring sites of uniparental disomy in follicular and transformed follicular lymphoma

“…The application of this approach to other malignancies has not only revealed copy number changes but has also uncovered the presence of large regions of homozygosity in the absence of copy number change. [14][15][16][17][18] Such regions, which have been termed acquired uniparental disomy (aUPD) or isodisomy, appear to be due to mitotic recombination between the two chromosomal homologues 19 and are undetectable by CGH array technology. These events can result in the selection of daughter cells made homozygous for a pre-existing mutation.…”