Elevated tolerance to aneuploidy in cancer cells: estimating the fitness effects of chromosome number alterations by in silico modelling of somatic genome evolution.
Valind, Anders LU
; Jin, Yuesheng
LU
and Gisselsson Nord, David
LU
(2013)
In PLoS ONE
8(7).
- Abstract
- An unbalanced chromosome number (aneuploidy) is present in most malignant tumours and has been attributed to mitotic mis-segregation of chromosomes. However, recent studies have shown a relatively high rate of chromosomal mis-segregation also in non-neoplastic human cells, while the frequency of aneuploid cells remains low throughout life in most normal tissues. This implies that newly formed aneuploid cells are subject to negative selection in healthy tissues and that attenuation of this selection could contribute to aneuploidy in cancer. To test this, we modelled cellular growth as discrete time branching processes, during which chromosome gains and losses were generated and their host cells subjected to selection pressures of various... (More)
- An unbalanced chromosome number (aneuploidy) is present in most malignant tumours and has been attributed to mitotic mis-segregation of chromosomes. However, recent studies have shown a relatively high rate of chromosomal mis-segregation also in non-neoplastic human cells, while the frequency of aneuploid cells remains low throughout life in most normal tissues. This implies that newly formed aneuploid cells are subject to negative selection in healthy tissues and that attenuation of this selection could contribute to aneuploidy in cancer. To test this, we modelled cellular growth as discrete time branching processes, during which chromosome gains and losses were generated and their host cells subjected to selection pressures of various magnitudes. We then assessed experimentally the frequency of chromosomal mis-segregation as well as the prevalence of aneuploid cells in human non-neoplastic cells and in cancer cells. Integrating these data into our models allowed estimation of the fitness reduction resulting from a single chromosome copy number change to an average of ≈30% in normal cells. In comparison, cancer cells showed an average fitness reduction of only 6% (p = 0.0008), indicative of aneuploidy tolerance. Simulations based on the combined presence of chromosomal mis-segregation and aneuploidy tolerance reproduced distributions of chromosome aberrations in >400 cancer cases with higher fidelity than models based on chromosomal mis-segregation alone. Reverse engineering of aneuploid cancer cell development in silico predicted that aneuploidy intolerance is a stronger limiting factor for clonal expansion of aneuploid cells than chromosomal mis-segregation rate. In conclusion, our findings indicate that not only an elevated chromosomal mis-segregation rate, but also a generalised tolerance to novel chromosomal imbalances contribute to the genomic landscape of human tumours. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/3955516
- author
- Valind, Anders
LU
; Jin, Yuesheng
LU
and Gisselsson Nord, David
LU
- organization
- publishing date
- 2013
- type
- Contribution to journal
- publication status
- published
- subject
- in
- PLoS ONE
- volume
- 8
- issue
- 7
- article number
- e70445
- publisher
- Public Library of Science (PLoS)
- external identifiers
-
- wos:000322167900128
- pmid:23894657
- scopus:84880802922
- pmid:23894657
- ISSN
- 1932-6203
- DOI
- 10.1371/journal.pone.0070445
- language
- English
- LU publication?
- yes
- id
- 0ba9e280-326a-477b-b35f-67b49f0ca7a6 (old id 3955516)
- alternative location
- http://www.ncbi.nlm.nih.gov/pubmed/23894657?dopt=Abstract
- date added to LUP
- 2016-04-01 15:01:05
- date last changed
- 2022-03-22 03:03:38
@article{0ba9e280-326a-477b-b35f-67b49f0ca7a6,
abstract = {{An unbalanced chromosome number (aneuploidy) is present in most malignant tumours and has been attributed to mitotic mis-segregation of chromosomes. However, recent studies have shown a relatively high rate of chromosomal mis-segregation also in non-neoplastic human cells, while the frequency of aneuploid cells remains low throughout life in most normal tissues. This implies that newly formed aneuploid cells are subject to negative selection in healthy tissues and that attenuation of this selection could contribute to aneuploidy in cancer. To test this, we modelled cellular growth as discrete time branching processes, during which chromosome gains and losses were generated and their host cells subjected to selection pressures of various magnitudes. We then assessed experimentally the frequency of chromosomal mis-segregation as well as the prevalence of aneuploid cells in human non-neoplastic cells and in cancer cells. Integrating these data into our models allowed estimation of the fitness reduction resulting from a single chromosome copy number change to an average of ≈30% in normal cells. In comparison, cancer cells showed an average fitness reduction of only 6% (p = 0.0008), indicative of aneuploidy tolerance. Simulations based on the combined presence of chromosomal mis-segregation and aneuploidy tolerance reproduced distributions of chromosome aberrations in >400 cancer cases with higher fidelity than models based on chromosomal mis-segregation alone. Reverse engineering of aneuploid cancer cell development in silico predicted that aneuploidy intolerance is a stronger limiting factor for clonal expansion of aneuploid cells than chromosomal mis-segregation rate. In conclusion, our findings indicate that not only an elevated chromosomal mis-segregation rate, but also a generalised tolerance to novel chromosomal imbalances contribute to the genomic landscape of human tumours.}},
author = {{Valind, Anders and Jin, Yuesheng and Gisselsson Nord, David}},
issn = {{1932-6203}},
language = {{eng}},
number = {{7}},
publisher = {{Public Library of Science (PLoS)}},
series = {{PLoS ONE}},
title = {{Elevated tolerance to aneuploidy in cancer cells: estimating the fitness effects of chromosome number alterations by in silico modelling of somatic genome evolution.}},
url = {{https://lup.lub.lu.se/search/files/4301280/4146025}},
doi = {{10.1371/journal.pone.0070445}},
volume = {{8}},
year = {{2013}},
}