title: A model for random genetic damage directing selection of diploid or aneuploid tumours.
abstract: OBJECTIVE
  To test whether genetic instability may determine whether tumours become aneuploid or diploid.
  
  
  METHODS
  We have identified genes needed for cell survival or replication by combining Affymetrix gene expression array data from 12 experimental cell lines with in silico GEO+GNF and expO databases. Specific loss of heterozygosis (LOHs), chromosomal abnormalities (called derivative chromosomes) and numbers of normal homologues were identified by SNP and SKY analyses. Random gene losses were calculated under the assumption that bi-allelic MMR gene inactivation causes a 20-fold increase in rate of gene loss.
  
  
  RESULTS
  There were ∼1.23 × 10(4) genes widely dispersed throughout the genome and possibly expressed by all cells for survival or proliferation, many of these genes performed housekeeping functions. Conservation of the genes may explain the complete haploid genomes found for 15 different cell types and derivative chromosomes selectively retained in aneuploid cancer cell lines after LOH formations, and normal homologue losses. Loss of cell survival/replication genes was calculated to be higher in colon stem cells of carriers of MMR gene mutations than carriers of APC gene mutations.
  
  
  CONCLUSIONS
  Random loss of cell survival/replication genes was calculated to be low enough for colon stem cells with APC gene mutations to 'select' LOH and derivative chromosome combinations favouring tumour cell proliferation. However, cell survival/replication gene loss was calculated to be too high for colonic stem cells lacking MMR genes to survive chromosomal instability, explaining why MMR mutations only produce tumours with diploid chromosome cells.
authors.affiliation: Program in Bioinformatics and Proteomics/Genomics, The University of Toledo, Toledo, OH, USA.
authors.forename: P S
authors.initials: PS
authors.lastname: Bazeley
authors.forename: A L
authors.initials: AL
authors.lastname: Nestor Kalinoski
authors.forename: J A
authors.initials: JA
authors.lastname: Ways
authors.forename: S-T
authors.initials: ST
authors.lastname: Liu
authors.forename: R S
authors.initials: RS
authors.lastname: Ramdath
authors.forename: S-i
authors.initials: SI
authors.lastname: Matsui
authors.forename: D C
authors.initials: DC
authors.lastname: Allison
mesh_terms: D000483:Alleles; D000782:Aneuploidy; D045744:Cell Line, Tumor; D002470:Cell Survival; D043171:Chromosomal Instability; D002869:Chromosome Aberrations; D002875:Chromosomes / Q000648:ultrastructure; D004171:Diploidy; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D008954:Models, Biological; D008957:Models, Genetic; D009154:Mutation; D009369:Neoplasms / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D013234:Stem Cells / Q000166:cytology