Chromosome missegregation causes colon cancer by APC loss of heterozygosity

Abstract

A longstanding hypothesis in the field of cancer biology is that aneuploidy causes cancer by promoting loss of chromosomes that contain tumor suppressor genes. By crossing aneuploidyprone Bub1 hypomorphic mice onto a heterozygous null background for p53, we provided conclusive evidence for this idea.(1) Surprisingly, the tumors that developed in this model had not just lost the chromosome 11 copy harboring wild-type p53, but had also gained an extra copy of chromosome 11 bearing the p53 null allele. Here we report that a similar chromosome-reshuffling blueprint drives colonic tumorigenesis in Bub1 hypomorphic mice that are heterozygous for Apc(Min), but now involving chromosome 18. These extended studies highlight that in order for whole chromosome instability to drive tumorigenesis, it needs to establish tumor suppressor gene loss of heterozygosity while retaining two copies of the other genes on the chromosome. Additional restrictions seem to apply to whole chromosome instability as a cancer causing mechanism, which will be discussed in this paper.

Figure 1

Proposed mechanism for LOH of p53 in thymocytes of Bub1 deficient animals. when a p53^+/- thymocyte enters into mitosis, it has two copies each of the p53 null and wild-type allele. Under normal situations, each daughter cell will receive one mutant allele and one wild-type allele, thereby maintaining the heterozygous p53 condition (not shown). However, due to insufficiencies of Bub1 and a weakened mitotic checkpoint, nondisjunction or aberrant segregation of sister chromatids occurs, leading to daughter cells that obtain two copies of the p53 null allele in potentially one (top) or two (bottom) steps.

Figure 2

Colon cancer of Bub1^-/H/Apc^Min/+ mice is driven by loss of chromosome 18 harboring the Apc⁺ locus and gain of an extra chromosome 18 harboring the Apc^Min allele. Haplotypes of tail tissue (N) from the father (a Bub1^-/H/Apc^Min/+ mouse) and mothers (Bub1^H/H/Apc^+/+) generating Bub1^-/H/Apc^Min/+ offspring heterozygous at 4 markers in tail (N) and normal colon (C) DNa. Colon tumors (t) of these animals have reverted to being homozygous for chromosome 18 containing the Apc^Min allele, which was inherited from their father.

Figure 3

Hypothetical models for how timing of w-CiN gene mutations may influence tumorigenesis. (a) Models in which neoplastic growth is initiated by mutation of a cancer-critical gene (other than a w-CiN gene). in scenario 1 (red line), tumor progression is driven by mutations that promote cell growth and survival. these mutations counteract the inhibiting effects of chromosome imbalances. So once w-CiN occurs, it may rapidly promote LOH and tumor advancement because only the tumor-promoting effects of aneuploidy are experienced in this tissue. in scenario 2 (blue line), w-CiN mutations may occur prior to those mutations that promote growth and survival, thereby leading to tumor cell growth inhibition (or reduced survival). the acquisition of additional mutations needed to bypass this inhibition may delay tumor development for prolonged periods of time, but after these changes occur, the underlying w-CiN mutation may rapidly promote LOH and tumorigenesis. So the timing of w-CiN gene defects may be critical to its impact on tumor progression. (B) Models prone to develop aneuploidy due to germline mutations in the mitotic checkpoint have different tissue-specific tumor susceptibilities in combination with particular tumor suppressor gene haplo-insufficiencies. in certain tissues (green line), such as thymocytes or colon epithelial cells of Bub1 deficient animals, w-CiN promotes the early loss of the chromosome containing the wild-type allele of tumor suppressor genes especially important for preventing neoplasia in that tissue, thereby accelerating the rapid onset of tumors. in other tissues (orange line), such as prostate epithelial cells of Bub1^-/H mice, aneuploidy initially has detrimental effects on cell growth and survival. a selective pressure exists to bypass these adverse effects by acquiring new mutations. Once cells have acquired these changes, aneuploidy due to w-CiN may promote LOH of tumor suppressor genes.