Journal
CYTOGENETIC AND GENOME RESEARCH
Volume 133, Issue 2-4, Pages 190-201Publisher
KARGER
DOI: 10.1159/000322480
Keywords
Aneuploidy; Cancer; Computer simulation; Multipolar mitosis; Non-disjunction; Trisomy
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Funding
- Swedish Childhood Cancer Foundation
- Swedish Cancer Society
- Swedish National Research Council
- Lund University
- Gunnar Nilsson Cancer Foundation
- Crafoord Foundation
- Erik-Philip Sorensen Foundation
- Lundgren Foundation
- Schyberg Foundation
- Medical Faculty at Lund University
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Whole chromosome gain is the most common type of gross genomic abnormality observed in human tumors. It is particularly frequent in lympho-haematopoietic and embryonic neoplasms, where trisomies and tetrasomies are typically present together with few or no other cytogenetic imbalances, resulting in hyperdiploid chromosome numbers. Despite the high prevalence of whole chromosome gains in neoplastic cells, their mechanism of origin remains disputed. Here, 4 potential models for the generation of whole chromosome gains are reviewed: (1) loss of chromosomes from the tetraploid level, (2) sequential sister chromatid non-disjunction, (3) multipolar mitosis coupled to sister chromatid non-disjunction, and (4) multipolar mitosis coupled to incomplete cytokinesis. Each of these mechanisms may in theory result in the generation of hyperdiploid neoplastic clones, but none of them were single-handedly able to reproduce the scenario of chromosome copy number alterations in tumors when cell populations resulting from these models were simulated in silico and compared to published cytogenetic data. To develop models for the generation of whole chromosome gains further, it is critical to improve our knowledge of the principles of clonal selection in tumors and of the baseline rate of chromosome segregation errors in human cells. To illustrate this, a model combining multipolar mitosis coupled to incomplete cytokinesis with a low rate of baseline sister chromatid non-disjunction was shown readily to reproduce copy number distributions in hyperdiploid karyotypes from human tumors. Copyright (C) 2010 S. Karger AG, Basel
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