Cancer Cytogenetics

Abstract

The development and progression of cancer is often associated with the acquisition of nonrandom chromosome aberrations. These can produce changes in gene loci, resulting in either the deregulated expression of an oncogene, the production of a chimaeric fusion gene or inactivation of a tumour suppressor gene (TSG). Chromosome aberrations are particularly important in the diagnosis, prognosis, progression, monitoring and treatment of acute and chronic leukaemia, small round cell tumours and central nervous system tumours. Numerical chromosome changes typically result in gain or loss of a few chromosomes, but can also produce changes in ploidy. Translocations, mostly affecting oncogenes, account for the majority of disease‐specific structural chromosome aberrations, whereas deletions are more important in TSGs. Knowledge of the nature and mechanisms of action of the genes involved is important in understanding how they contribute to the genesis, promotion and progression of this complex disease.

Key concepts

  • Chimaeric gene fusion – the most frequent, recurrent oncogenic change usually produced via chromosome translocation. Two previously separate and independent genes are fused to form a single unique contiguous gene, and the resultant gene product has oncogenic properties.

  • Oncogene deregulation – juxtapositioning of an oncogene with the enhancer region of a T‐cell receptor gene or an Immunoglobulin gene results in overexpression of the oncogene protein product. This is most commonly a result of a chromosome translocation.

  • Oncogene amplification – a selective, unscheduled increase in gene copy number enabling a cell to meet the increased transcriptional demands of neoplastic transformation. This is seen as double minutes or as a chromosome duplication.

  • Tumour suppressor gene inactivation – removal of the growth control functions of a TSG either by mutation or loss, after which the cell may fail to keep a cancer from developing, transforming the cell to a cancer phenotype.

  • Loss of heterozygosity – the key mechanism of inactivation of a TSG. At a locus heterozygous for a deleterious mutant allele and a normal allele, a deletion or other mutation in the normal allele renders the cell hemizygous or homozygous for the deleterious allele.

Keywords: oncogene; tumour suppressor gene; translocation; deletion; duplication

Figure 1.

Illustration shows BCRABL fusion gene following t(9;22) Philadelphia translocation. In chronic myeloid leukaemia (CML) breakage is within the M‐BCR region and this is shown to produce an 8.5‐kb fusion transcript, which generates a 210‐kDa fusion protein. In acute lymphoblastic leukaemia (ALL), the 22q break is typically within the m‐BCR region. This produces a 7.5‐kb fusion transcript, which generates a smaller 190‐kDa fusion protein. Note that, in both cases, the critical fusion transcript is on the der(22).

Figure 2.

Illustration showing juxtapositioning of MYC from 8q to constant (C) region of the IGH locus at 14q32. Note that the entire coding region (exons 2 and 3) of MYC is translocated in a head‐to‐head (5′ to 5′) manner. The consequence is upregulation of a structurally normal cmyc protein.

Figure 3.

Karyotype of Ewing sarcoma tumour with the pathognomonic t(11;22)(q24;q12). This case also contains 1q gain in the form of an additional isochromosome of 1q. The karyotype here is defined as ‘simple’, i.e. with fewer than five independent chromosome changes. The interphase FISH image shows EWSR1 gene rearrangement. A break‐apart Vysis EWSR1FISH probe demonstrates splitting of the 5′EWSR1 (green) signal from the 3′EWSR1 (red) signal. The normal (fusion) EWSR1 locus is seen as a yellow signal.

Figure 4.

FISH images using a Zytovision PAX7FKHR probe kit in a case of alveolar rhabdomyosarcoma with PAX7FKHR amplification. The interphase cell (left) shows multiple yellow fusion signals of the PAX7 (green) and FKHR (red) probes. The metaphase cell (right) shows PAX7FKHR fusion signals present on supernumerary double minute structures (yellow). Only one discrete PAX7 signal on the normal chromosome 1 and only one discrete FKHR signal on the normal chromosome 13 is seen. One chromosome 1 homologue and one chromosome 13 homologue is deleted for PAX7 and FKHR, respectively. It is assumed that a t(1;13) translocation has originally occurred and the resultant PAX7FKHR fusion product has broken off from the derivative chromosome 13 to produce the episomic double minutes.

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References

de Alava E and Gerald WL (2000) Molecular biology of the Ewing's sarcoma/primitive neuroectodermal tumour family. Journal of Clinical Oncology 18(1): 204–213.

Aldape K (2007) Clinicopathologic aspects of 1p/19q loss and the diagnosis of oligodendroglioma. Archives of Pathology & Laboratory Medicine 131: 242–251.

Aplan P (2006) Chromosomal translocations involving the MLL gene: molecular mechanisms. DNA Repair (Amst) 5(9–10): 1265–1272.

Aster JC and Longtine JA (2002) Detection of BCL2 rearrangements in follicular lymphoma. The American Journal of Pathology 160: 759–763.

Baldus CD, Mrozek K, Marcucci G and Bloomfield CD (2007) Clinical outcome of de novo AML patients with normal cytogenetics is affected by molecular genetic alterations: a concise review. British Journal of Haematology 137: 387–400.

Balmain A, Gray J and Ponder B (2003) The genetics and genomics of cancer. Nature Genetics 33: 238–244.

Basecke J, Whelan JT, Griesinger F and Bertrand FE (2006) The MLL partial tandem duplication in AML. British Journal of Haematology 135: 438–449.

Bown N (2001) Neuroblastoma tumour genetics: clinical and biological aspects. Journal of Clinical Pathology 54: 897–910.

Bown N, Cotterill S, Lastowska M et al. (1999) Gain of chromosome arm 17q and adverse outcome in patients with neuroblastoma. The New England Journal of Medicine 340: 1954–1961.

Buchonnet G, Jardin F, Jean N et al. (2002) Distribution of BCL2 breakpoints in follicular lymphoma and correlation with clinical features: specific subtypes or same disease? Leukaemia 16: 1852–1856.

Dal Cin P, Atkins L, Ford C et al. (2001) Amplification of AML1 in childhood ALLs. Genes, Chromosomes & Cancer 30: 244–249.

Daser A and Rabbitts TH (2005) The versatile mixed lineage leukaemia gene MLL and its many associations in leukaemogenesis. Seminars in Cancer Biology 15: 175–188.

Faderl S, Talpaz M, Estrov Z et al. (1999) The biology of chronic myeloid leukaemia. The New England Journal of Medicine 341(3): 164–172.

Garcia‐Casado Z, Cervera J, Verdeguer A et al. (2006) High level amplification of the RUNX1 gene in two cases of childhood ALL. Cancer Genetics and Cytogenetics 170: 171–174.

Greaves M, Maia AT, Wiemels JL and Ford AM (2003) Leukaemia in twins: lessons in natural history. Blood 102: 2321–2333.

Guo C, White PS, Hogarty MD et al. (2000) Deletion of 11q23 is a frequent event in the evolution of MYCN single copy, high risk neuroblastomas. Medical and Pediatric Oncology 35: 544–546.

Hattinger CM, Potschger U, Tarkkanen M et al. (2002) Prognostic impact of chromosomal aberrations in Ewing tumours. British Journal of Cancer 5: 1763–1769.

Hecht J and Aster J (2000) Molecular biology of Burkitt's lymphoma. Journal of Clinical Oncology 18: 3703–3721.

Jabbour E, Cortes JE, Giles FJ, O'Brien S and Kantarjian HM (2007) Current and emerging treatment options in CML. Cancer 109: 2171–2181.

Kallioniemi A (2008) CGH microarrays and cancer. Current Opinion in Biotechnology 19: 36–40.

Kallioniemi A, Kallioniemi OP, Sudar D et al. (1992) Comparative genomic hybridisation for molecular cytogenetic analysis of solid tumours. Science 258: 818–819.

Knudsen AG (1971) Mutation and cancer: statistical study of retinoblastoma. Proceedings of the National Academy of Sciences of the USA 68: 820–823.

Lastowska M, Cotterill S, Bown N et al. (2002) Breakpoint position on 17q identifies the most aggressive neuroblastoma tumours. Genes, Chromosomes & Cancer 34: 428–436.

Litzow MR (2006) Imatinib resistance: obstacles and opportunities. Archives of Pathology & Laboratory Medicine 130: 669–679.

Loeb LA, Loeb KR and Anderson JP (2003) Multiple mutations and cancer. Proceedings of the National Academy of Sciences of the USA 100: 776–781.

Mora J, Cheung NK, Kushner BH et al. (2000) Clinical categories of neuroblastoma are associated with different patterns of loss of heterozygosity on chromosome arm 1p. Journal of Molecular Diagnostics 2: 37–46.

Mrozek K, Marcucci G, Paschka P, Whitman SP and Bloomfield CD (2008) Clinical relevance of mutations and gene‐expression changes in adult AML with normal cytogenetics: are we ready for a prognostically prioritised molecular classification. Blood 109: 431–448.

Nowell PC and Hungerford DA (1960) A minute chromosome in human chronic granulocytic leukaemia. Science 132: 1497–1501.

Plantaz D, Vandesompele J, Van Roy N et al. (2001) Comparative genomic hybridisation (CGH) analysis of stage 4 neuroblastoma reveals high frequency of 11q deletion in tumours lacking MYCN amplification. International Journal of Cancer 91: 680–686.

Roberts P, Burchill SA, Brownhill S et al. (2008) Ploidy and karyotype complexity are powerful prognostic indicators in the Ewing's sarcoma family of tumours: a study by the UKCCG and CCLG. Genes, Chromosomes & Cancer 47: 207–220.

Rubnitz JE, Pui C‐H and Downing JR (1999) The role of TEL fusion genes in paediatric leukaemias. Leukaemia 13: 6–13.

Savelyeva L and Schwab M (2001) Amplification of oncogenes revisited: from expression profiling to clinical application. Cancer Letters 167: 115–123.

Sherr CJ (2004) Principles of tumour suppression. Cell 116: 235–246.

Shimada A, Taki T, Tabuchi K et al. (2008) Tandem duplications of MLL and FLT3 are correlated with poor prognosis in paediatric AML: a study of the Japanese childhood AML cooperative group. Pediatric Blood & Cancer 50: 264–269.

Simon T, Spitz R, Hero B, Berthold F and Faldum A (2006) Risk estimation in localized unresectable single copy MYCN neuroblastoma by the status of chromosomes 1p and 11q. Cancer Letters 237: 215–222.

Sinclair PB, Nacheva EP, Leversha M et al. (2000) Large deletions at the t(9;22) breakpoint are common and may identify a poor prognosis subgroup of patients with CML. Blood 95: 738–743.

Sorensen PHB, Lynch JC, Qualman SJ et al. (2002) PAX3‐FKHR and PAX7‐FKHR gene fusions are prognostic indicators in alveolar rhabdomyosarcoma: a report from the children's oncology group. Journal of Clinical Oncology 20: 2672–2679.

Speck NA and Gilliland DG (2002) Core‐binding factors in haematopoiesis and leukaemia. Nature Reviews Cancer 2: 502–513.

Spitz R, Hero B, Ernestus K and Berthold F (2003) Gain of distal chromosome arm 17q is not associated with poor prognosis in neuroblastoma. Clinical Cancer Research 9: 4835–4840.

Ting AH, McGarvey KM and Baylin SB (2006) The cancer epigenome – components and functional correlates. Genes & Development 20: 3215–3231.

Valent A, Le Roux G, Barrois M et al. (2002) MYCN overrepresentation detected in primary neuroblastoma tumours cells without amplification. The Journal of Pathology 198: 495–501.

Vaz de Campos MG, Montesano FT, Rodrigues MM and de Lourdes Lopes Ferrari Chauffaille M (2007) Clinical implications of der(9q) deletions detected through dual fusion fluorescence in situ hybridisation in patients with CML. Cancer Genetics and Cytogenetics 178: 49–56.

Williamson D, Lu Y‐J, Gordon T et al. (2005) Relationship between MYCN copy number and expression in rhabdomyosarcomas and correlation with adverse prognosis in alveolar subtype. Journal of Clinical Oncology 23: 880–888.

Xia SJ, Pressey JG and Barr FG (2002) Molecular pathogenesis of rhabdomyosarcoma. Cancer Biology & Therapy 1(2): 97–104.

Zhang B, Pan X, Cobb GP and Anderson TA (2007) microRNAs as oncogenes and tumour suppressors. Developmental Biology 302: 1–12.

Further Reading

Aplan PD (2006) Causes of oncogenic chromosomal translocation. Trends in Genetics 22: 46–55.

Burchill SA and Roberts P (2006) Molecular and genetic abnormalities in tumours of the Ewing's sarcoma family (EFST). In: Sherbet GV (ed.) The Molecular and Cellular Pathology of Cancer Progression and Prognosis, pp. 221–233. Kerala, India: Research Signpost.

Campbell LJ (2005) Cytogenetics of lymphomas. Pathology 37: 493–507.

Cortes JE, Talpaz M and Kantarjian H (1996) Chronic myelogenous leukaemia: a review. American Journal of Medicine 100: 555–570.

Lazar A, Abruzzo LV, Pollock RE, Lee S and Czerniak B (2006) Molecular diagnosis of sarcomas. Archives of Pathology & Laboratory Medicine 130: 1199–1207.

Mitelman F (2000) Recurrent chromosome aberrations in cancer. Mutation Research 462: 247–253.

Mrozek K, Heeram NA and Bloomfield CD (2004) Cytogenetics of acute leukaemia. Blood Reviews 18: 115–136.

Pinkel D and Albertson DG (2005) Array CGH and its applications in cancer. Nature Genetics 37: 511–517.

Rowley JD (2001) Chromosome translocations: dangerous liaisons revisited. Nature Reviews Cancer 1: 245–250.

Tefferi A, Dewald GW, Litzow MI et al. (2005) CML: current application of cytogenetic and molecular testing for diagnosis and treatment. Mayo Clinic Proceedings 80: 390–402.

Vogelstein B and Kinzler KW (2004) Cancer genes and the pathways they control. Nature Medicine 10: 789–799.

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Roberts, Paul(Dec 2008) Cancer Cytogenetics. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0001476.pub2]