Aurea Mediocritas: The Importance of a Balanced Genome
21
Citation
152
Reference
10
Related Paper
Citation Trend
Abstract:
Gianluca Varetti1,2, David Pellman1,2,3 and David J. Gordon1 1Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115 2Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115 3Howard Hughes Medical Institute, Chevy Chase, Maryland 20815-6789 Correspondence: David_Pellman{at}dfci.harvard.eduKeywords:
Chromosome instability
Chromosome instability
Cite
Citations (30)
Chromosome instability
Cite
Citations (97)
Abstract Aneuploidy, an aberrant chromosome number, has been recognized as a common characteristic of cancer cells for more than 100 years and has been suggested as a cause of tumorigenesis for nearly as long. However, this proposal had remained untested due to the difficulty of selectively generating aneuploidy without causing other damage. Using Cenp-E heterozygous animals, which develop whole chromosome aneuploidy in the absence of other defects, we have found that aneuploidy promotes tumorigenesis in some contexts and inhibits it in others. These findings confirm that aneuploidy can act oncogenically and reveal a previously unsuspected role for aneuploidy as a tumor suppressor. [Cancer Res 2007;67(21):10103–5]
Cite
Citations (187)
Cite
Citations (29)
Genomic instability (GIN) is a hallmark of cancer cells that facilitates the acquisition of mutations conferring aggressive or drug-resistant phenotypes during cancer evolution. Chromosomal instability (CIN) is a form of GIN that involves frequent cytogenetic changes leading to changes in chromosome copy number (aneuploidy). While both CIN and aneuploidy are common characteristics of cancer cells, their roles in tumor initiation and progression are unclear. On the one hand, CIN and aneuploidy are known to provide genetic variation to allow cells to adapt in changing environments such as nutrient fluctuations and hypoxia. Patients with constitutive aneuploidies are more susceptible to certain types of cancers, suggesting that changes in chromosome copy number could positively contribute to cancer evolution. On the other hand, chromosomal imbalances have been observed to have detrimental effects on cellular fitness and might trigger cell cycle arrest or apoptosis. Furthermore, mouse models for CIN have led to conflicting results. Taken together these findings suggest that the relationship between CIN, aneuploidy and cancer is more complex than what was previously anticipated. Here we review what is known about this complex ménage à trois, discuss recent evidence suggesting that aneuploidy, CIN and GIN together promote a vicious cycle of genome chaos. Lastly, we propose a working hypothesis to reconcile the conflicting observations regarding the role of aneuploidy and CIN in tumorigenesis.
Chromosome instability
Chromothripsis
Cite
Citations (231)
Abstract In order to evaluate the significance of cytometric aneuploidy in molar placentas, we analyzed 197 hydatidiform moles by flow cytometry using formalin‐fixed, paraffin‐embedded tissues. Of 150 complete moles (CMs), 110 were diploid, 26 were tetraploid, and 14 were aneuploid (non‐triploid/tetraploid aneuploid). Of 47 partial moles (PMs), 44 were triploid and 3 were diploid. We could not find any histologic differences among the diploid, tetraploid, and aneuploid CMs. We found that flow cytometric DNA analysis was very helpful to differentiate CM from PM. Persistent diseases developed in 12 of 69 CMs (17.4%) (9 of 47 diploid and 3 of 14 tetraploid CMs) and in none of 26 PMs (0%). Four diploid and 2 tetraploid CMs were invasive and one each with diploid and tetraploid CM developed choriocarcinoma and none of 8 aneuploid CMs had sequelae; however, there was no correlation between DNA ploidy and clinical outcome in the CMs. These results suggest that cytometric aneuploidy (non‐diploidy) in CMs is not an independent predictor of persistent disease. © 1995 Wiley‐Liss, Inc.
Cite
Citations (16)
Aneuploidy decreases cellular fitness, yet it is also associated with cancer, a disease of enhanced proliferative capacity. To investigate one mechanism by which aneuploidy could contribute to tumorigenesis, we examined the effects of aneuploidy on genomic stability. We analyzed 13 budding yeast strains that carry extra copies of single chromosomes and found that all aneuploid strains exhibited one or more forms of genomic instability. Most strains displayed increased chromosome loss and mitotic recombination, as well as defective DNA damage repair. Aneuploid fission yeast strains also exhibited defects in mitotic recombination. Aneuploidy-induced genomic instability could facilitate the development of genetic alterations that drive malignant growth in cancer.
Chromosome instability
Cite
Citations (394)
Cancers have a clonal origin, yet their chromosomes and genes are non-clonal or heterogeneous due to an inherent genomic instability. However, the cause of this genomic instability is still debated. One theory postulates that mutations in genes that are involved in DNA repair and in chromosome segregation are the primary causes of this instability. But there are neither consistent correlations nor is there functional proof for the mutation theory. Here we propose aneuploidy, an abnormal number of chromosomes, as the primary cause of the genomic instability of neoplastic and preneoplastic cells. Aneuploidy destabilizes the karyotype and thus the species, independent of mutation, because it corrupts highly conserved teams of proteins that segregate, synthesize and repair chromosomes. Likewise it destabilizes genes. The theory explains 12 of 12 specific features of genomic instability: (1) Mutagenic and non-mutagenic carcinogens induce genomic instability via aneuploidy. (2) Aneuploidy coincides and segregates with preneoplastic and neoplastic genomic instability. (3) Phenotypes of genomically unstable cells change and even revert at high rates, compared to those of diploid cells, via aneuploidy-catalyzed chromosome rearrangements. (4) Idiosyncratic features of cancers, like immortality and drug-resistance, derive from subspecies within the 'polyphyletic' diversity of individual cancers. (5) Instability is proportional to the degree of aneuploidy. (6) Multilateral chromosomal and genetic instabilities typically coincide, because aneuploidy corrupts multiple targets simultaneously. (7) Gene mutation is common, but neither consistent nor clonal in cancer cells as predicted by the aneuploidy theory. (8) Cancers fall into a near-diploid (2 N) class of low instability, a near 1.5 N class of high instability, or a near 3 N class of very high instability, because aneuploid fitness is maximized either by minimally unstable karyotypes or by maximally unstable, but adaptable karyotypes. (9) Dominant phenotypes, because of aneuploid genotypes. (10) Uncertain developmental phenotypes of Down and other aneuploidy syndromes, because supply-sensitive, diploid programs are destabilized by products from aneuploid genes supplied at abnormal concentrations; the maternal age-bias for Down's would reflect age-dependent defects of the spindle apparatus of oocytes. (11) Non-selective phenotypes, e.g., metastasis, because of linkage with selective phenotypes on the same chromosomes. (12) The target, induction of genomic instability, is several 1000-fold bigger than gene mutation, because it is entire chromosomes. The mutation theory explains only a few of these features. We conclude that the transition of stable diploid to unstable aneuploid cell species is the primary cause of preneoplastic and neoplastic genomic instability and of cancer, and that mutations are secondary.
Chromosome instability
Chromothripsis
Cite
Citations (132)
Chromosome instability
Cite
Citations (16)
Chromosome instability
Chromothripsis
Cite
Citations (180)