A key feature of cancer chromosomes and genomes is their high level of dynamics and the ability to constantly evolve. This unique characteristic forms the basis of genetic heterogeneity necessary for cancer formation, which presents major obstacles to current cancer diagnosis and treatment. It has been difficult to integrate such dynamics into traditional models of cancer progression. In this conceptual piece, we briefly discuss some of the recent exciting progress in the field of cancer genomics and genome research. In particular, a re-evaluation of the previously disregarded non-clonal chromosome aberrations (NCCAs) is reviewed, coupled with the progress of the detection of sub-chromosomal aberrations with array technologies. Clearly, the high level of genetic heterogeneity is directly caused by genome instability that is mediated by stochastic genomic changes, and genome variations defined by chromosome aberrations are the driving force of cancer progression. In addition to listing various types of non-recurrent chromosomal aberrations, we discuss the likely mechanism underlying cancer chromosome dynamics. Finally, we call for further examination of the features of dynamic genome diseases including cancer in the context of systems biology and the need to integrate this new knowledge into basic research and clinical applications. This genome centric concept will have a profound impact on the future of biological and medical research.

1.
Albertson DG: Gene amplification in cancer. Trends Genet 22:447–55 (2006).
2.
Albertson DG, Collins C, McCormick F, Gray JW: Chromosome aberrations in solid tumors. Nat Genet 34:369–376 (2003).
3.
Albiez H, Cremer M, Tiberi C, Vecchio L, Schermelleh L, et al: Chromatin domains and the interchromatin compartment form structurally defined and functionally interacting nuclear networks. Chromosome Res 14:707–733 (2006).
4.
Atkin NB, Baker MC: Are human cancers ever diploid – or often trisomic? Conflicting evidence from direct preparation and cultures. Cytogenet Cell Genet 53:58–60 (1990).
5.
Baldwin C, Garnis C, Zhang L, Rosin MP, Lam WL: Multiple microalterations detected at high frequency in oral cancer. Cancer Res 65:7561–7567 (2005).
6.
Bignell G, Smith R, Hunter C, Stephens P, Davies H, et al: Sequence analysis of the protein kinase gene family in human testicular germ-cell tumors of adolescents and adults. Genes Chromosomes Cancer 45:42–46 (2006).
7.
Czene K, Lichtenstein P, Hemminki K: Environmental and heritable causes of cancer among 9.6 million individuals in the Swedish Family-Cancer Database. Int J Cancer 99:260–266 (2002).
8.
Davies JJ, Wilson IM, Lam WL: Array CGH technologies and their applications to cancer genomes. Chromosome Res 13:237–248 (2005).
9.
Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Reese SF, et al: Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 344:1038–1042 (2001).
10.
Duesberg P, Rasnick D: Aneuploidy, the somatic mutation that makes cancer a species of its own. Cell Motil Cytoskeleton 47:81–107 (2000).
11.
Duker NJ: Chromosome breakage syndromes and cancer. Am J Med Genet 115:125–129 (2002).
12.
Fearon ER, Vogelstein B: A genetic model for colorectal tumorigenesis. Cell 61:759–767 (1990).
13.
Feuk L, Carson AR, Scherer SW: Structural variation in the human genome. Nat Rev Genet 7:85–97 (2006).
14.
Foijer F, te Riele H: Check, double check: the G2 barrier to cancer. Cell Cycle 5:831–836 (2006).
15.
Gao CF, Xie Q, Su YL, Koeman J, Khoo SK, Gustafson M, et al: Proliferation and invasion: plasticity in tumor cells. Proc Natl Acad Sci USA 102:10528–10533 (2005).
16.
Garnis C, Buys T, Lam W: Genetic alteration and gene expression modulation during cancer progression. Mol Cancer 3:9 (2004).
17.
Guasconi V, Souidi M, Ait-Si-Ali S: Nuclear positioning, gene activity and cancer. Cancer Biol Ther 4:134–138 (2005).
18.
Heim S, Mitelman F: Cancer Cytogenetics. 2nd ed. (Wiley-Liss, New York 1995).
19.
Heng HH: Cancer genome sequencing: the challenges ahead. BioEssays 29:783–794 (2007a).
20.
HengHH: Elimination of altered karyotypes by sexual reproduction preserves species identity. Genome 50:517–524 (2007b).
21.
Heng HH, Tsui LC: High resolution free chromatin/DNA fiber fluorescent in situ hybridization. J Chromatogr A 806:219–229 (1998).
22.
Heng H, Chen WY, Wang YC: Effects of pingyanymycin on chromosomes: a possible structural basis for chromosome aberration. Mutat Res 199:199–205 (1988).
23.
Heng HH, Squire J, Tsui LC: High-resolution mapping of mammalian genes by in situ hybridization to free chromatin. Proc Natl Acad Sci USA 89:9509–9513 (1992).
24.
Heng HH, Chamberlain J, Shi XM, Spyropoulos B, Tsui L-C, Moens PB: Regulation of meiotic chromatin loop size by chromosomal position. Proc Natl Acad Sci USA 93:2795–2800 (1996).
25.
Heng HH, Spyropoulos B, Moens PB: FISH technology in chromosome and genome research. Bioessays 19:75–84 (1997).
26.
Heng HH, Krawetz SK, Lu W, Bremer S, Liu G, Ye CJ: Re-defining the chromatin loop domain. Cytogenet Cell Genet 93:155–161 (2001a).
27.
Heng HH, Liu G, Lu W, Bremer S, Ye CJ, Hughes M, Moens P: Spectral karyotyping (SKY) of mouse meiotic chromosomes. Genome 44:293–298 (2001b).
28.
Heng HH, Ye CJ, Yang F, Ebrahim S, Liu G, Bremer SW, et al: Analysis of marker or complex chromosomal rearrangements present in pre- and post-natal karyotypes utilizing a combination of G-banding, spectral karyotyping and fluorescence in situ hybridization. Clin Genet 63:358–367 (2003).
29.
Heng HH, Goetze S, Ye CJ, Liu G, Stevens JB, Bremer SW, et al: Chromatin loops are selectively anchored using scaffold/matrix-attachment regions. J Cell Sci 117:999–1008 (2004a).
30.
Heng HH, Stevens J, Liu G, Bremer SW, Ye CJ: Imaging genome abnormalities in cancer research. Cell Chromosomes 3:1 (2004b).
31.
Heng HH, Liu G, Bremer S, Ye JK, Stevens J, Ye CJ: Clonal and non clonal chromosome aberrations and genome variation/aberration. Genome 49:195–204 (2006a).
32.
Heng HH, Stevens JB, Liu G, Bremer SW, Ye KJ, Reddy PV, et al: Stochastic cancer progression driven by non-clonal chromosome aberrations. J Cell Physiol 208:461–472 (2006b).
33.
Heng HH, Bremer SW, Stevens J, Ye KJ, Miller F, Liu G, Ye CJ: Cancer progression by non-clonal chromosome aberrations. J Cell Biochem 98:1424–1435 (2006c).
34.
Heppner GH, Miller FR: The cellular basis of tumor progression. Intl Rev Cytol 177:1–56 (1998).
35.
Hoglund, M, Sall T, Heim S, Mitelman F, Mandahl N, Fadl-Elmula I: Identification of cytogenetic subgroups and karyotypic pathways in transitional cell carcinoma. Cancer Res 61:8241–8246 (2001).
36.
Hoglund M, Frigyesi A, Sall T, Gisselsson D, Mitelman F: Statistical behavior of complex cancer karyotypes. Genes Chromosomes Cancer 42:327–341 (2005).
37.
Iafrate AJ, Feuk L, Rivera MN, Listewnik ML, Donahoe PK, et al: Detection of large-scale variation in the human genome. Nat Genet 36:949–951 (2004).
38.
ISCN (1995): An International System for Human Cytogenetic Nomenclature, Mitelman F (ed) (S Karger, Basel 1995).
39.
ISCN (2005): An International System for Human Cytogenetic Nomenclature, Shaffer LG, Tommerup N (eds). (S Karger, Basel 2005).
40.
Johansson B, Fioretos T, Mitelman F: Cytogenetic and molecular genetic evolution of chronic myeloid leukemia. Acta Haematol 107:76–94 (2002).
41.
Khanna KK, Jackson SP: DNA double-strand breaks: signaling, repair and the cancer connection. Nat Genet 27:247–254 (2001).
42.
King M: Species Evolution. The Role of Chromosome Change (Cambridge University Press, Cambridge 1993).
43.
Kitano H: Systems biology: a brief overview. Science 295:1662–1664 (2002).
44.
Kohn M, Hogel J, Vogel W, Minich P, Kehrer-Sawatzki H, et al: Reconstruction of a 450- My-old ancestral vertebrate protokaryotype. Trends Genet 22:203–210 (2006).
45.
Losi L, Baisse B, Bouzourene H, Benhattar J: Evolution of intratumoral genetic heterogeneity during colorectal cancer progression. Carcinogenesis 26:916–922 (2005).
46.
Mai S, Garini Y: The significance of telomeric aggregates in the interphase nuclei of tumor cells. J Cell Biochem 97:904–915 (2006).
47.
Mantripragada KK, Buckley PG, de Stahl TD, Dumanski JP: Genomic microarrays in the spotlight. Trends Genet 20:87–94 (2004).
48.
Marcus GF: The Birth of the Mind. (Basic Books, New York 2004).
49.
McFadden D, Friedman J: Chromosome abnormalities in human beings. Mutat Res 396:129–140 (1997).
50.
Michor F, Iwasa Y, Vogelstein B, Lengauer C, Nowak MA: Can chromosomal instability initiate tumorigenesis? Semin Cancer Biol 15:43–49 (2005).
51.
Miller OJ, Therman E: Human Chromosomes. (Springer, New York 2003).
52.
Mitelman F: Recurrent chromosome aberrations in cancer. Mutat Res 462:247–253 (2000).
53.
Murphy WJ, Larkin DM, Everts-van der Wind A, Bourque G, Tesler G, et al: Dynamics of mammalian chromosome evolution inferred from multispecies comparative maps. Science 309:613–617 (2005).
54.
Navarro A, Barton NH: Chromosomal speciation and molecular divergence–accelerated evolution in rearranged chromosomes. Science 300:321–324 (2003).
55.
Rowley JD: The critical role of chromosome translocations in human leukemias. Annu Rev Genet 32:495–519 (1998).
56.
Rowley JD: Chromosome translocations: dangerous liaisons revisited. Nat Rev Cancer 1:245–250 (2001).
57.
Rubin H: Degree and kinds of selection in spontaneous neoplastic transformation: an operational analysis. Proc Natl Acad Sci USA 102: 9276–9281 (2005).
58.
Sandberg AA: Cancer cytogenetics for clinicians. CA: Cancer J Clinicians 44:136–159 (1994).
59.
Sands AT, Suraokar MB, Sanchez A, Marth JE, Donehower LA, Bradley A: p53 deficiency does not affect the accumulation of point mutations in a transgene target. Proc Natl Acad Sci USA 92:8517–8521 (1995).
60.
Schrock E, du Manoir S, Velman T, Schoell B, Wienberg J, et al: Multicolor spectral karyotyping of human chromosomes. Science 273:494–497 (1996).
61.
Sjoblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber T, et al: The consensus coding sequences of human breast and colorectal cancers. Science 314:268–274 (2006).
62.
Stephens P, Edkins S, Davies H, Greenman C, Cox C, et al: A screen of the complete protein kinase gene family identifies diverse patterns of somatic mutations in human breast cancer. Nat Genet 37:590–592 (2005).
63.
Stevens JB, Savasan S, Liu G, Bremer S, Atanasovski M, Xu W, et al: Cell death by chromosome elimination: Characterization of drug induced chromosomal fragmentation. ASHG 2004 Annual Meeting, program number 326 (2004).
64.
Stevens JB, Liu G, BremerSW, Ye KJ, XuW, et al: Mitotic cell death by chromosome fragmentation. Cancer Res 67:7686–7694 (2007).
65.
Tomlins SA, Rhodes DR, Perner S, Dhanasekaran SM, Mehra R, et al: Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 310:644–648 (2005).
66.
Wu X, Avni D, Chiba T, Yan F, Zhao Q, et al: SV40 T antigen interacts with Nbs1 to disrupt DNA replication control. Genes Dev 18:1305–1316 (2004).
67.
Ye CJ, Lu W, Liu G, Bremer SW, Wang YA, et al: The combination of SKY and specific loci detection with FISH or immunostaining. Cytogenet Cell Genet 93:195–202 (2001).
68.
Ye CJ, Stevens J, Liu G, Ye J, Yang F, Bremer SW, Heng HH: Combined multicolor-FISH and immunostaining. Cytogenet Genome Res 114:227–234 (2006).
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