A model for genetic complementation controlling the chromosomal abnormalities and loss of heterozygosity formation in cancer.
The relationship between the apparently random chromosomal changes found in aneuploidy and the genetic instability driving the progression of cancer is not clear. We report a test of the hypothesis that aneuploid chromosomal abnormalities might be selected to preserve cell-survival genes during loss of heterozygosity (LOH) formations which eliminate tumor suppressor genes. The LOHs and structurally abnormal chromosomes present in the aneuploid LoVo (colon), A549 (lung), SUIT-2 (pancreas), and LN-18 (glioma) cancer cell lines were identified by single nucleotide polymorphisms (SNPs) and Spectral Karyotyping (SKY). The Mann-Whitney U and chi square tests were used to evaluate possible differences in chromosome numbers and abnormalities between the cell lines, with two-tailed P values of <0.01 being considered significant. The cell lines differed significantly in chromosome numbers and frequency of structurally abnormal chromosomes. The SNP analysis revealed that each cell line contained at least a haploid set of somatic chromosomes, consistent with our hypothesis that cell-survival genes are widely scattered throughout the genome. Further, over 90% of the chromosomal abnormalities seemed to be selected, often after LOH formation, for gene-dosage compensation or to provide heterozygosity for specific chromosomal regions. These results suggest that the chromosomal changes of aneuploidy are not random, but may be selected to provide gene-dosage compensation and/or retain functional alleles of cell-survival genes during LOH formation.
Nestor
A L
AL
Department of Surgery and The University of Toledo Advanced Microscopy and Imaging Center, The University of Toledo, Health Science Campus Toledo, Toledo, OH 43614-5804, USA.
Hollopeter
S L
SL
Matsui
S-I
SI
Allison
D
D
D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D002869:Chromosome Aberrations; D002877:Chromosomes, Human / Q000235:genetics; D018628:Gene Dosage; D005816:Genetic Complementation Test; D006801:Humans; D019656:Loss of Heterozygosity / Q000235:genetics*; D008297:Male; D008957:Models, Genetic; D009369:Neoplasms / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D032681:Spectral Karyotyping; D014178:Translocation, Genetic