General aspects of cytogenetic analysis in hematologic malignancies
- Yanming Zhang, MD
Yanming Zhang, MD
- Director of Cytogenetics Laboratory
- Memorial Sloan Kettering Cancer Center
- Michelle M Le Beau, PhD
Michelle M Le Beau, PhD
- Professor of Medicine
- University of Chicago Pritzker School of Medicine
The malignant cells in many patients with leukemia, lymphoma, or another malignant hematologic disease have acquired clonal chromosomal abnormalities. Some specific cytogenetic abnormalities are closely, and sometimes uniquely, associated with morphologically and clinically distinct subsets of leukemia or lymphoma, as well as with their prognosis.
Because of the ease of obtaining and processing bone marrow or peripheral blood samples, more information is available about the relationship between cytogenetic abnormalities and the pathogenesis and natural history of the leukemias than for other malignancies. However, improvements in cell culture, processing techniques, and the application of molecular techniques have permitted the identification of a number of recurring abnormalities in solid tumors as well.
The detection of clonal cytogenetic abnormalities can be useful:
●To establish the specific diagnosis, such as the Philadelphia chromosome in chronic myeloid leukemia
●To distinguish between benign reactive lymphoid or myeloid hyperplasia and a monoclonal malignant proliferationTo continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- McGowan-Jordan J, Simons A, Schmid M. ISCN: 2016: An International System for Human Cytogenetic Nomenclature, Karger S (Ed), Basel, Switzerland 2016.
- Cancer Genome Atlas Research Network, Ley TJ, Miller C, et al. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med 2013; 368:2059.
- Roberts KG, Morin RD, Zhang J, et al. Genetic alterations activating kinase and cytokine receptor signaling in high-risk acute lymphoblastic leukemia. Cancer Cell 2012; 22:153.
- Patel JP, Gönen M, Figueroa ME, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med 2012; 366:1079.
- Gozzetti A, Le Beau MM. Fluorescence in situ hybridization: uses and limitations. Semin Hematol 2000; 37:320.
- Zenz T, Mertens D, Döhner H, Stilgenbauer S. Molecular diagnostics in chronic lymphocytic leukemia - pathogenetic and clinical implications. Leuk Lymphoma 2008; 49:864.
- Buño I, Moreno-Lopez E, Diez-Martin JL. Sequential fluorescence in situ hybridization for the quantification of minimal residual disease in recipient cells after sex-mismatched allogeneic stem cell transplantation. Br J Haematol 2002; 118:349.
- Munshi NC, Anderson KC, Bergsagel PL, et al. Consensus recommendations for risk stratification in multiple myeloma: report of the International Myeloma Workshop Consensus Panel 2. Blood 2011; 117:4696.
- Marcucci G, Haferlach T, Döhner H. Molecular genetics of adult acute myeloid leukemia: prognostic and therapeutic implications. J Clin Oncol 2011; 29:475.
- Nucifora G, Larson RA, Rowley JD. Persistence of the 8;21 translocation in patients with acute myeloid leukemia type M2 in long-term remission. Blood 1993; 82:712.
- Maciejewski JP, Mufti GJ. Whole genome scanning as a cytogenetic tool in hematologic malignancies. Blood 2008; 112:965.
- Mullighan CG, Downing JR. Genome-wide profiling of genetic alterations in acute lymphoblastic leukemia: recent insights and future directions. Leukemia 2009; 23:1209.
- Mullighan CG, Su X, Zhang J, et al. Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. N Engl J Med 2009; 360:470.
- Godley LA, Cunningham J, Dolan ME, et al. An integrated genomic approach to the assessment and treatment of acute myeloid leukemia. Semin Oncol 2011; 38:215.
- Mullighan CG, Phillips LA, Su X, et al. Genomic analysis of the clonal origins of relapsed acute lymphoblastic leukemia. Science 2008; 322:1377.
- Harrison CJ. Targeting signaling pathways in acute lymphoblastic leukemia: new insights. Hematology Am Soc Hematol Educ Program 2013; 2013:118.
- Papaemmanuil E, Gerstung M, Malcovati L, et al. Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood 2013; 122:3616.
- Greaves MF, Wiemels J. Origins of chromosome translocations in childhood leukaemia. Nat Rev Cancer 2003; 3:639.
- Rosenbauer F, Tenen DG. Transcription factors in myeloid development: balancing differentiation with transformation. Nat Rev Immunol 2007; 7:105.
- Godley LA, Sukhanova M, Raca G, et al. Cytogenetics and Genetic Abnormalities. In: Williams Hematology, 9th ed, Kaushansky K, Lichtman MA, Prchal JT, et al (Eds), McGraw-Hill Education, 2015.
- Falini B, Mason DY. Proteins encoded by genes involved in chromosomal alterations in lymphoma and leukemia: clinical value of their detection by immunocytochemistry. Blood 2002; 99:409.
- Dyer MJ. The pathogenetic role of oncogenes deregulated by chromosomal translocation in B-cell malignancies. Int J Hematol 2003; 77:315.
- Druker BJ, Sawyers CL, Kantarjian H, 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 2001; 344:1038.
- Zhang Y, Rowley JD. Chronic myeloid leukemia: current perspectives. Clin Lab Med 2011; 31:687.
- O'Hare T, Eide CA, Deininger MW. New Bcr-Abl inhibitors in chronic myeloid leukemia: keeping resistance in check. Expert Opin Investig Drugs 2008; 17:865.
- Hochhaus A, Larson RA, Guilhot F, et al. Long-Term Outcomes of Imatinib Treatment for Chronic Myeloid Leukemia. N Engl J Med 2017; 376:917.
- Mistry AR, Pedersen EW, Solomon E, Grimwade D. The molecular pathogenesis of acute promyelocytic leukaemia: implications for the clinical management of the disease. Blood Rev 2003; 17:71.
- Mrózek K, Bloomfield CD. Clinical significance of the most common chromosome translocations in adult acute myeloid leukemia. J Natl Cancer Inst Monogr 2008; :52.
- Grimwade D, Hills RK, Moorman AV, et al. Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. Blood 2010; 116:354.
- Harrison CJ, Hills RK, Moorman AV, et al. Cytogenetics of childhood acute myeloid leukemia: United Kingdom Medical Research Council Treatment trials AML 10 and 12. J Clin Oncol 2010; 28:2674.
- Goyama S, Mulloy JC. Molecular pathogenesis of core binding factor leukemia: current knowledge and future prospects. Int J Hematol 2011; 94:126.
- Harrison CJ. Cytogenetics of paediatric and adolescent acute lymphoblastic leukaemia. Br J Haematol 2009; 144:147.
- Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016; 127:2391.
- Cavé H, van der Werff ten Bosch J, Suciu S, et al. Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia. European Organization for Research and Treatment of Cancer--Childhood Leukemia Cooperative Group. N Engl J Med 1998; 339:591.
- Mitterbauer M, Kusec R, Schwarzinger I, et al. Comparison of karyotype analysis and RT-PCR for AML1/ETO in 204 unselected patients with AML. Ann Hematol 1998; 76:139.
- Krauter J, Wattjes MP, Nagel S, et al. Real-time RT-PCR for the detection and quantification of AML1/MTG8 fusion transcripts in t(8;21)-positive AML patients. Br J Haematol 1999; 107:80.
- Buonamici S, Ottaviani E, Testoni N, et al. Real-time quantitation of minimal residual disease in inv(16)-positive acute myeloid leukemia may indicate risk for clinical relapse and may identify patients in a curable state. Blood 2002; 99:443.
- Heim S, Mitelman F. Cancer Cytogenetics, 4th ed, John Wiley & Sons, Inc., New Jersey 2015.
- Bochtler T, Stölzel F, Heilig CE, et al. Clonal heterogeneity as detected by metaphase karyotyping is an indicator of poor prognosis in acute myeloid leukemia. J Clin Oncol 2013; 31:3898.
- The Mitelman Database of Chromosome Aberrations in Cancer. (cgap.nci.nih.gov/Chromosomes/Mitelman).
- GENERAL DEFINITIONS
- Standard notation for reciprocal translocations
- Definition of clonality
- EXAMINATION OF TUMOR SPECIMENS
- Obtaining the sample
- Methods of detection
- - Metaphase cytogenetic analysis
- - FISH
- - Polymerase chain reaction
- - Microarray analysis and sequencing
- GENETIC CONSEQUENCES OF CHROMOSOMAL TRANSLOCATION
- Mechanisms of altered gene function
- - Impaired regulation of gene expression
- - Novel fusion proteins
- Clinical implications
- - Quantitative changes
- - Qualitative changes
- - Selection of treatment