A model for genetic complementation controlling the chromosomal abnormalities and loss of heterozygosity formation in cancer

Abstract

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.

A model for random genetic damage directing selection of diploid or aneuploid tumours

“…SNP‐maps can be classified as: (i) heterozygous with red (heterozygous) and blue (homozygous) SNPs along the entire chromosome length, indicating presence of DNA from both parental homologues; (ii) broken‐chromosome LOHs resulting from loss of a large fragment(s) from one parental homologue, with the LOH region (blue dots only) found where the DNA from only one homologue remains; and (iii) whole‐chromosome LOHs, or only a haploid genome of one parental homologue remaining (blue dots only), following complete loss of the other parental homologue (Fig. 2) (15). The occasional heterozygous SNPs (red dots) found in whole‐chromosome SNP‐maps may be due to assay errors or to represent small, translocated DNA pieces from opposing parental homologues.…”

“…Four prostate cancer cell lines (DU‐145, PC‐3, 22Rv1, LNCap), a benign prostate cell line (RWPE), three lung cancer cell lines (A549, H520, Calu‐6), two benign lung fibroblast lines (CCD‐34Lu, MRC‐5), a pancreatic cancer cell line (SUIT‐2) and a benign skin cell line (BUD‐8) made up the 12 experimental cell lines used. Each of the cell lines was obtained from the American Type Culture Collection (http://www.atcc.org), except for SUIT‐2, which had been previously characterized (15). All cell lines were expanded as monolayer cultures.…”

“…Previously reported SNP and SKY results achieved from A549, LN‐18, and SUIT‐2 lines (15) were combined with SNP and SKY data from PC‐3 and DU145 cell lines, for in‐depth analysis of five aneuploid cancer cell lines. Examined by SKY, there were 24, 29, 30, 36 and 40 karyotypes for A549, LN‐18, PC‐3, DU‐145 and SUIT‐2 cell lines respectively, at the Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY.…”

“…Now, we have tested and expanded a hypothesis that aneuploidy is ‘selected’ by the majority of solid tumours to preserve genes and/or other DNA regions essential for tumour cell growth in derivative chromosomes and to eliminate selectively, genes and/or other DNA regions retarding cell proliferation in LOHs (15). In support of this model, we found a core of ∼1.23 × 10 4 genes expressed by all cells in a screen of 885 different cell types.…”

Chromosomes during Cell Division

“…Paradoxically, aneuploidy is also often found in cancer cells that have gained growth advantages and divide out of control. The normally deleterious effects of simple aneuploidy (gain or loss of whole chromosomes) in diploid cells are compensated for in cancer cells (Nestor et al, 2007). These compensation mechanisms may include polypoidisation or gross chromosomal structural alterations in addition to specific genetic or epigenetic modifications on oncogenes or tumour suppressors.…”