title: Elevated tolerance to aneuploidy in cancer cells: estimating the fitness effects of chromosome number alterations by in silico modelling of somatic genome evolution.
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.
authors.affiliation: Department of Clinical Genetics, Lund University and Skåne Regional and University Laboratories, Lund, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Valind
authors.forename: Yuesheng
authors.initials: Y
authors.lastname: Jin
authors.forename: David
authors.initials: D
authors.lastname: Gisselsson
mesh_terms: D000782:Aneuploidy; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D002869:Chromosome Aberrations; D020090:Chromosome Segregation / Q000235:genetics; D060965:Clonal Evolution / Q000235:genetics / Q000502:physiology; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D059785:Karyotype; D008297:Male
references.citation: PLoS One. 2011;6(8):e23018
references.pmid: 21857983
references.citation: Nat Med. 2009 May;15(5):577-83
references.pmid: 19396175
references.citation: Atherosclerosis. 2001 Dec;159(2):281-7
references.pmid: 11730807
references.citation: Mech Ageing Dev. 1995 Apr 21;80(1):11-23
references.pmid: 7564557
references.citation: Cell. 2010 Oct 1;143(1):71-83
references.pmid: 20850176
references.citation: Proc Natl Acad Sci U S A. 2001 Oct 23;98(22):12683-8
references.pmid: 11675499
references.citation: Cancer Res. 2002 Oct 15;62(20):5939-46
references.pmid: 12384560
references.citation: Neurobiol Dis. 2009 May;34(2):212-20
references.pmid: 19344645
references.citation: Proc Natl Acad Sci U S A. 2010 Nov 23;107(47):20489-93
references.pmid: 21059955
references.citation: J Cell Biol. 2008 Feb 25;180(4):665-72
references.pmid: 18283116
references.citation: Cancer Res. 1976 Feb;36(2 Pt 1):467-75
references.pmid: 1260746
references.citation: Nature. 2012 Jan 18;481(7381):287-94
references.pmid: 22258607
references.citation: Cell. 2011 Feb 18;144(4):499-512
references.pmid: 21315436
references.citation: Gastroenterology. 2012 Jan;142(1):25-8
references.pmid: 22057114
references.citation: PLoS One. 2007 Jun 27;2(6):e558
references.pmid: 17593959
references.citation: PLoS One. 2009 Aug 10;4(8):e6564
references.pmid: 19668340
references.citation: Nature. 2009 Jul 9;460(7252):278-82
references.pmid: 19506557
references.citation: J Comp Neurol. 2010 Oct 1;518(19):3981-4000
references.pmid: 20737596
references.citation: PLoS Comput Biol. 2007 Nov;3(11):e225
references.pmid: 17997597
references.citation: Cancer Genet Cytogenet. 2001 Apr 1;126(1):34-8
references.pmid: 11343776
references.citation: Cancer Res. 2002 May 1;62(9):2675-80
references.pmid: 11980667
references.citation: Nature. 1997 Apr 10;386(6625):623-7
references.pmid: 9121588
references.citation: Genes Chromosomes Cancer. 2005 Apr;42(4):327-41
references.pmid: 15645488
references.citation: Exp Cell Res. 1997 Aug 25;235(1):161-9
references.pmid: 9281365
references.citation: Cancer Res. 2003 Nov 1;63(21):7094-7
references.pmid: 14612501
references.citation: Nature. 2000 Aug 10;406(6796):641-5
references.pmid: 10949306
references.citation: Int J Cancer. 2003 Nov 10;107(3):365-74
references.pmid: 14506735
references.citation: Nature. 2010 Nov 11;468(7321):321-5
references.pmid: 20962780
references.citation: Cytogenet Genome Res. 2002;98(1):22-8
references.pmid: 12584437
references.citation: Am J Hum Genet. 1995 Nov;57(5):1143-50
references.pmid: 7485166
references.citation: Nat Med. 1999 Jan;5(1):11-2
references.pmid: 9883827
references.citation: Cancer Genet Cytogenet. 2000 Aug;121(1):17-21
references.pmid: 10958935
references.citation: Science. 2008 Oct 31;322(5902):703-9
references.pmid: 18974345
references.citation: Trends Genet. 2011 Nov;27(11):446-53
references.pmid: 21872963
references.citation: J Clin Invest. 2012 Sep;122(9):3307-15
references.pmid: 22863619
references.citation: Cancer Res. 2004 Oct 1;64(19):6941-9
references.pmid: 15466185
references.citation: Science. 2011 Sep 30;333(6051):1895-8
references.pmid: 21960636
references.citation: Fertil Steril. 2005 Nov;84(5):1395-400
references.pmid: 16275234
references.citation: Methods Cell Sci. 2001;23(1-3):23-8
references.pmid: 11741141
references.citation: Fertil Steril. 2005 Nov;84(5):1328-34
references.pmid: 16275225
references.citation: PLoS Genet. 2012;8(5):e1002719
references.pmid: 22615582
references.citation: Proc Natl Acad Sci U S A. 2000 May 9;97(10):5357-62
references.pmid: 10805796
references.citation: Mutagenesis. 1999 Nov;14(6):563-8
references.pmid: 10567031
references.citation: Clin Cancer Res. 2007 Nov 15;13(22 Pt 1):6593-602
references.pmid: 18006759
references.citation: J Cell Biol. 2010 Feb 8;188(3):369-81
references.pmid: 20123995
references.citation: Nat Genet. 2012 May 06;44(6):651-8
references.pmid: 22561519
references.citation: Hereditas. 1985;102(1):33-8
references.pmid: 3988540
references.citation: Placenta. 2011 Mar;32 Suppl 2:S136-41
references.pmid: 21281965
references.citation: Nature. 1970 Jan 17;225(5229):281-2
references.pmid: 5409983
references.citation: Proc Natl Acad Sci U S A. 2005 Apr 12;102(15):5541-6
references.pmid: 15809428