CGH-based microarray detection of cryptic and novel copy number alterations and balanced translocations in cytogenetically abnormal cases of b-cell all

Roger A. Schultz, Karen Tsuchiya, Aubry Furrow, Marilyn L. Slovak, Lisa D. McDaniel, Meaghan Wall, Eric Crawford, Yi Ning, Reza Saleki, Min Fang, Victoria Cawich, Caitlin E. Johnson, Sara L. Minier, Nicholas J. Neill, S. Annie Morton, Steve Byerly, Urvashi Surti, Theresa C. Brown, Blake C. Ballif, Lisa G. Shaffer

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, USA.
Empire Genomics, Buffalo, USA.
Fred Hutchinson Cancer Research Center, Seattle, USA.
Genetics Associates, Inc., Nashville, USA.
Johns Hopkins University School of Medicine, Baltimore, USA.
Magee-Womens Hospital, University of Pittsburgh Medical Center, Pittsburgh, USA.
Pathology Associates Medical Laboratories (PAML), Spokane, USA.
Paw Print Genetics, Genetic Veterinary Sciences, Inc., Spokane, USA.
Seattle Children’s Hospital, Seattle, USA.
Signature Genomic Laboratories, PerkinElmer, Inc., Spokane, USA.
Signature Genomic Laboratories, PerkinElmer, Inc., Spokane, USA;.
Sonora Quest Laboratories, Tempe, USA.
Victorian Cancer Cytogenetics Service, St. Vincent’s Hospital Melbourne, Fitzroy, Australia.

DOI: 10.4236/health.2013.55A004                

Abstract

Acute lymphoblastic leukemia (ALL) is the most common malignancy in children, with the majority of cases being of precursor B-cell phenoltype. Conventional cytogenetic analysis plays an important role in the diagnosis of B-cell ALL, identifying characteristic chromosomal abnormalities associated with a given prognosis therein facilitating optimized treatment. The more recent introduction of microarray technology to the analysis of B-cell ALL has afforded both higher resolution for the detection of known abnormalities and an ability to identify novel copy number abnormalities (CNAs) with potential clinical relevance. In the current study, microarray analysis was performed on 20 cytogenetically abnormal B-cell ALL cases (10 pediatric and 10 adult), while a novel microarray-based balanced-translocation detection methodology (translocation CGH or tCGH) was applied to that subset of cases with a known or suspected recurrent balanced translocation. Standard microarray analysis identified that CNAs was not detected by previous conventional cytogenetics in 75% (15/20) cases. tCGH identified 9/9 (100%) balanced translocations defining BCR/ABL1 (x4), ETV6/RUNX1 (x3), and MLL/AFF1 (x2) breakpoints with high resolution. The results illustrate the improved molecular detail afforded by these technologies and a comparison of translocation breakpoints, CNAs and patient age offers new insights into tumor biology with potential prognostic significance.

Keywords

Acute Lymphoblastic Leukemia; B-Cell ALL; Microarray; Balanced Translocation; Translocation CGH; Hematologic Malignancies

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	Pui, C.H., Pei, D., Sandlund, J.T., Ribeiro, R.C., Rubnitz, J.E., Raimondi, S.C., et al. (2010) Long-term results of St Jude Total Therapy Studies 11, 12, 13A, 13B, and 14 for childhood acute lymphoblastic leukemia. Leukemia, 24, 371-382. doi:10.1038/leu.2009.252
[2]	Pui, C.H., Campana, D., Pei, D., Bowman, W.P., Sandlund, J.T., Kaste, S.C., et al. (2009) Treating childhood acute lymphoblastic leukemia without cranial irradiation. The New England Journal of Medicine, 360, 2730-2741. doi:10.1056/NEJMoa0900386
[3]	Dougherty, M.J., Wilmoth, D.M., Tooke, L.S., Shaikh, T.H., Gai, X., Hakonarson, H., et al. (2011) Implementation of high resolution single nucleotide polymorphism array analysis as a clinical test for patients with hematologic malignancies. Cancer Genetics, 204, 26-38. doi:10.1016/j.cancergencyto.2010.10.007
[4]	Fielding, A.K., Richards, S.M., Chopra, R., Lazarus, H.M., Litzow, M.R., Buck, G., et al. (2007) Outcome of 609 adults after relapse of acute lymphoblastic leukemia (ALL); an MRC UKALL12/ECOG 2993 study. Blood, 109, 944-950. doi:10.1182/blood-2006-05-018192
[5]	Nguyen, K., Devidas, M., Cheng, S.C., La, M., Raetz, E.A., Carroll, W.L., et al. (2008) Factors influencing survival after relapse from acute lymphoblastic leukemia: A Children’s Oncology Group study. Leukemia, 22, 2142- 2150. doi:10.1038/leu.2008.251
[6]	Pui, C.H., Relling, M.V. and Downing, J.R. (2004) Acute lymphoblastic leukemia. The New England Journal of Medicine, 350, 1535-1548. doi:10.1056/NEJMra023001
[7]	Malempati, S., Gaynon, P.S., Sather, H., La, M.K. and Stork, L.C. (2007) Outcome after relapse among children with standard-risk acute lymphoblastic leukemia: Children’s Oncology Group study CCG-1952. Journal of Clinical Oncology, 25, 5800-5807. doi:10.1200/JCO.2007.10.7508
[8]	Pui, C.H., Robison, L.L. and Look, A.T. (2008) Acute lymphoblastic leukaemia. Lancet, 371, 1030-1043. doi:10.1016/S0140-6736(08)60457-2
[9]	Mullighan, C.G. (2011) New strategies in acute lymphoblastic leukemia: Translating advances in genomics into clinical practice. Clinical Cancer Research, 17, 396- 400. doi:10.1158/1078-0432.CCR-10-1203
[10]	Kawamata, N., Ogawa, S., Zimmermann, M., Kato, M., Sanada, M., Hemminki, K., et al. (2008) Molecular allelokaryotyping of pediatric acute lymphoblastic leukemias by high-resolution single nucleotide polymorphism oligonucleotide genomic microarray. Blood, 111, 776-784. doi:10.1182/blood-2007-05-088310
[11]	Kuiper, R.P., Schoenmakers, E.F., van Reijmersdal, S.V., Hehir-Kwa, J.Y., Van Kessel, A.G., Van Leeuwen, F.N., et al. (2007) High-resolution genomic profiling of childhood ALL reveals novel recurrent genetic lesions affecting pathways involved in lymphocyte differentiation and cell cycle progression. Leukemia, 21, 1258-1266. doi:10.1038/sj.leu.2404691
[12]	Mullighan, C.G., Goorha, S., Radtke, I., Miller, C.B., Coustan-Smith, E., Dalton, J.D., et al. (2007) Genomewide analysis of genetic alterations in acute lymphoblastic leukaemia. Nature, 446, 758-764. doi:10.1038/nature05690
[13]	Kuiper, R.P., Waanders, E., Van Der Velden, V.H., Van Reijmersdal, S.V., Venkatachalam, R., Scheijen, B., et al. (2010) IKZF1 deletions predict relapse in uniformly treated pediatric precursor B-ALL. Leukemia, 24, 1258-1264. doi:10.1038/leu.2010.87
[14]	White, M.K. and McCubrey, J.A. (2001) Suppression of apoptosis: Role in cell growth and neoplasia. Leukemia, 15, 1011-1021. doi:10.1038/sj.leu.2402143
[15]	Russell, L.J., Capasso, M., Vater, I., Akasaka, T., Bernard, O.A., Calasanz, M.J., et al. (2009) Deregulated expression of cytokine receptor gene, CRLF2, is involved in lymphoid transformation in B-cell precursor acute lymphoblastic leukemia. Blood, 114, 2688-2698.
[16]	Mullighan, C.G. (2010) Genetic Alterations in High-Risk B-Progenitor Acute Lymphoblastic Leukemia, in SIOP Education Book 2010: 42nd Congress of the International Society of Paediatric Oncology, Boston, USA, October 21-24, 2010, Agarwal, B.R., et al. Ed., International Society of Paediatric Oncology, SIOP (International Society of Paediatric Oncology), Eindhoven, 77-87.
[17]	Mullighan, C.G., Su, X., Zhang, J., Radtke, I., Phillips, L.A., Miller, C.B., et al. (2009) Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. The New England Journal of Medicine, 360, 470-480. doi:10.1056/NEJMoa0808253
[18]	Miller, D.T., Adam, M.P., Aradhya, S., Biesecker, L.G., Brothman, A.R., Carter, N.P., et al. (2010) Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. The American Journal of Human Genetics, 86, 749-764. doi:10.1016/j.ajhg.2010.04.006
[19]	Shaffer, L.G., Schultz, R.A. and Ballif, B.C. (2012) The use of new technologies in the detection of balanced translocations in hematologic disorders. Current Opinion in Genetics & Development, 22, 264-271. doi:10.1016/j.gde.2012.01.005
[20]	Greisman, H.A., Hoffman, N.G. and Yi, H.S. (2011) Rapid High-Resolution Mapping of Balanced Chromosomal Rearrangements on Tiling CGH Arrays. The Journal of Molecular Diagnostics, 13, 621-633. doi:10.1016/j.jmoldx.2011.07.005
[21]	Yu, L., Slovak, M.L., Mannoor, K., Chen, C., Hunger, S.P., Carroll, A.J., et al. (2011) Microarray detection of multiple recurring submicroscopic chromosomal aberrations in pediatric T-cell acute lymphoblastic leukemia. Leukemia, 25, 1042-1046. doi:10.1038/leu.2011.33
[22]	Kolquist, K.A., Schultz, R.A, Furrow, A., Brown, T.C., Han, J.Y., Campbell, L.J., et al. (2011) Microarray-based comparative genomic hybridization of cancer targets reveals novel, recurrent genetic aberrations in the myelodysplastic syndromes. Cancer Genetics, 204, 603-628. doi:10.1016/j.cancergen.2011.10.004
[23]	Mullighan, C.G. and Downing, J.R. (2009) Global genomic characterization of acute lymphoblastic leukemia. Seminars in Hematology, 46, 3-15. doi:10.1053/j.seminhematol.2008.09.005
[24]	Charrin, C., Thomas, X., Ffrench, M., Le, Q.H., Andrieux, J., Mozziconacci, M.J., et al. (2004) A report from the LALA-94 and LALA-SA groups on hypodiploidy with 30 to 39 chromosomes and near-triploidy: 2 possible expressions of a sole entity conferring poor prognosis in adult acute lymphoblastic leukemia (ALL). Blood, 104, 2444- 2451. doi:10.1182/blood-2003-04-1299
[25]	Moorman, A.V., Richards, S.M., Robinson, H.M., Strefford, J.C., Gibson, B.E., Kinsey, S.E., et al. (2007) Prognosis of children with acute lymphoblastic leukemia (ALL) and intrachromosomal amplification of chromosome 21 (iAMP21). Blood, 109, 2327-2330. doi:10.1182/blood-2006-08-040436
[26]	Moorman, A.V. (2012) The clinical relevance of chromosomal and genomic abnormalities in B-cell precursor acute lymphoblastic leukaemia. Blood Reviews. 26, 123- 135. doi:10.1016/j.blre.2012.01.001
[27]	Mullighan, C.G. and Downing, J.R. (2009) Genome-wide profiling of genetic alterations in acute lymphoblastic leukemia: Recent insights and future directions. Leukemia, 23, 1209-1218. doi:10.1038/leu.2009.18
[28]	Nutt, S.L., Eberhard, D., Horcher, M., Rolink, A.G. and Busslinger, M. (2001) Pax5 determines the identity of B cells from the beginning to the end of B-lymphopoiesis. International Reviews of Immunology, 20, 65-82. doi:10.3109/08830180109056723
[29]	Nebral, K., Denk, D., Attarbaschi, A., Konig, M., Mann, G., Haas, O.A., et al. (2009) Incidence and diversity of PAX5 fusion genes in childhood acute lymphoblastic leukemia. Leukemia, 23, 134-143. doi:10.1038/leu.2008.306
[30]	Mullighan, C.G., Miller, C.B., Radtke, I., Phillips, L.A., Dalton, J., Ma, J., et al. (2008) BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros. Nature, 453, 110-114. doi:10.1038/nature06866
[31]	Martinelli, G., Iacobucci, I., Storlazzi, C.T., Vignetti, M., Paoloni, F., Cilloni, D., et al. (2009) IKZF1 (Ikaros) deletions in BCR-ABL1-positive acute lymphoblastic leukemia are associated with short disease-free survival and high rate of cumulative incidence of relapse: A GIMEMA AL WP report. Journal of Clinical Oncology, 27, 5202- 5207. doi:10.1200/JCO.2008.21.6408
[32]	Bardet, V., Couque, N., Cattolico, L., Hetet, G., Devaux, I., Duprat, S., et al. (2002) Molecular analysis of nonrandom 8q12 deletions in acute lymphoblastic leukemia: Identification of two candidate genes. Genes Chromosomes Cancer, 33, 178-187. doi:10.1002/gcc.10014
[33]	Aliahmad, P., de la Torre, B. and Kaye, J. (2010) Shared dependence on the DNA-binding factor TOX for the development of lymphoid tissue-inducer cell and NK cell lineages. Nature Immunology, 11, 945-952. doi:10.1038/ni.1930
[34]	Tissing, W.J., Meijerink, J.P., den Boer, M.L. and Pieters, R. (2003) Molecular determinants of glucocorticoid sensitivity and resistance in acute lymphoblastic leukemia. Leukemia, 17, 17-25. doi:10.1038/sj.leu.2402733
[35]	Van Galen, J.C., Kuiper, R.P., Van Emst, L., Levers, M., Tijchon, E., Scheijen, B., et al. (2010) BTG1 regulates glucocorticoid receptor autoinduction in acute lymphoblastic leukemia. Blood, 115, 4810-4819. doi:10.1182/blood-2009-05-223081
[36]	Davies, S.M., Bhatia, S., Ross, J.A., Kiffmeyer, W.R., Gaynon, P.S., Radloff, G.A., et al. (2002) Glutathione S-transferase genotypes, genetic susceptibility, and outcome of therapy in childhood acute lymphoblastic leukemia. Blood, 100, 67-71. doi:10.1182/blood.V100.1.67
[37]	Takanashi, M., Morimoto, A., Yagi, T., Kuriyama, K., Kano, G., Imamura, T., et al. (2003) Impact of glutathione S-transferase gene deletion on early relapse in childhood B-precursor acute lymphoblastic leukemia. Haematologica, 88, 1238-1244.
[38]	Meissner, B., Stanulla, M., Ludwig, W.D., Harbott, J., Moricke, A., Welte, K., et al. (2004) The GSTT1 deletion polymorphism is associated with initial response to glucocorticoids in childhood acute lymphoblastic leukemia. Leukemia, 18, 1920-1923. doi:10.1038/sj.leu.2403521
[39]	Sulong, S., Moorman, A.V., Irving, J.A., Strefford, J.C., Konn, Z.J., Case, M.C., et al. (2009) A comprehensive analysis of the CDKN2A gene in childhood acute lymphoblastic leukemia reveals genomic deletion, copy number neutral loss of heterozygosity, and association with specific cytogenetic subgroups. Blood, 113, 100-107. doi:10.1182/blood-2008-07-166801
[40]	Bertin, R., Acquaviva, C., Mirebeau, D., Guidal-Giroux, C., Vilmer, E. and Cave, H. (2003) CDKN2A, CDKN2B, and MTAP gene dosage permits precise characterization of mono- and bi-allelic 9p21 deletions in childhood acute lymphoblastic leukemia. Genes Chromosomes Cancer, 37, 44-57. doi:10.1002/gcc.10188
[41]	Usvasalo, A., Savola, S., Raty, R., Vettenranta, K., Harila- Saari, A., Koistinen, P. et al. (2008) CDKN2A deletions in acute lymphoblastic leukemia of adolescents and young adults: An array CGH study. Leukemia Research, 32, 1228-1235. doi:10.1016/j.leukres.2008.01.014
[42]	Parker, H., An, Q., Barber, K., Case, M., Davies, T., Konn, Z. et al. (2008) The complex genomic profile of ETV6- RUNX1 positive acute lymphoblastic leukemia highlights a recurrent deletion of TBL1XR1. Genes Chromosomes Cancer, 47, 1118-1125. doi:10.1002/gcc.20613
[43]	Hodges, E., Krishna, M.T., Pickard, C. and Smith, J.L. (2003) Diagnostic role of tests for T cell receptor (TCR) genes. Journal of Clinical Pathology, 56, 1-11. doi:10.1136/jcp.56.1.1
[44]	Roberts, K.G. and Mullighan, C.G. (2011) How new advances in genetic analysis are influencing the understanding and treatment of childhood acute leukemia. Current Opinion in Pediatrics, 23, 34-40. doi:10.1097/MOP.0b013e3283426260
[45]	Schoumans, J., Johansson, B., Corcoran, M., Kuchinskaya, E., Golovleva, I., Grander, D., et al. (2006) Characterisation of dic(9;20)(p11-13;q11) in childhood B-cell precursor acute lymphoblastic leukaemia by tiling resolution array-based comparative genomic hybridisation reveals clustered breakpoints at 9p13.2 and 20q11.2. British Journal of Haematology, 135, 492-499. doi:10.1111/j.1365-2141.2006.06328.x
[46]	Strefford, J.C., Worley, H., Barber, K., Wright, S., Stewart, A.R., Robinson, H.M. et al. (2007) Genome complexity in acute lymphoblastic leukemia is revealed by array-based comparative genomic hybridization. Oncogenomics, 26, 4306-4318. doi:10.1038/sj.onc.1210190
[47]	Dewald, G.W., Ketterling, R.P., Wyatt, W.A. and Stupca, P.J. (2002) Cytogenetics studies in neoplastic hematologic disorders, in clinical laboratory medicine. In: McClatchey, K.D., Ed., Lippincott Williams & Wilkins, Philadelphia, 658-685.
[48]	Pui, C.H., Frankel, L.S., Carroll, A.J., Raimondi, S.C., Shuster, J.J., Head, D.R. et al. (1991) Clinical characteristics and treatment outcome of childhood acute lymphoblastic leukemia with the t(4;11)(q21;q23): A collaborative study of 40 cases. Blood, 77, 440-447.
[49]	Grimwade, D., Walker, H., Oliver, F., Wheatley, K., Harrison, C., Harrison, G., et al. (1998) The importance of diagnostic cytogenetics on outcome in AML: Analysis of 1,612 patients entered into the MRC AML 10 trial. The Medical Research Council Adult and Children’s Leukaemia Working Parties. Blood, 92, 2322-2333.
[50]	Raimondi, S.C., Chang, M.N., Ravindranath, Y., Behm, F.G., Gresik, M.V., Steuber, C.P., et al. (1999) Chromosomal abnormalities in 478 children with acute myeloid leukemia: Clinical characteristics and treatment outcome in a cooperative pediatric oncology group study-POG 8821. Blood, 94, 3707-3716.
[51]	Balgobind, B.V., Raimondi, S.C., Harbott, J., Zimmermann, M., Alonzo, T.A., Auvrignon, A., et al. (2009) Novel prognostic subgroups in childhood 11q23/MLL- rearranged acute myeloid leukemia: Results of an international retrospective study. Blood, 114, 2489-2496. doi:10.1182/blood-2009-04-215152
[52]	Johansson, B., Moorman, A.V., Haas, O.A., Watmore, A.E., Cheung, K.L., Swanton, S., et al. (1998) Hematologic malignancies with t(4;11)(q21;q23)—A cytogenetic, morphologic, immunophenotypic and clinical study of 183 cases. European 11q23 Workshop participants. Leukemia, 12, 779-787. doi:10.1038/sj.leu.2401012
[53]	Burmeister, T., Meyer, C., Schwartz, S., Hofmann, J., Molkentin, M., Kowarz, E., et al. (2009) The MLL recombinome of adult CD10-negative B-cell precursor acute lymphoblastic leukemia: Results from the GMALL study group. Blood, 113, 4011-4015. doi:10.1182/blood-2008-10-183483
[54]	Sandoval, C., Head, D.R., Mirro, J.Jr., Behm, F.G., Ayers, G.D. and Raimondi, S.C. (1992) Translocation t(9;11) (p21;q23) in pediatric de novo and secondary acute myeloblastic leukemia. Leukemia, 6, 513-519.
[55]	Hunger, S.P. (1996) Chromosomal translocations involveing the E2A gene in acute lymphoblastic leukemia: Clinical features and molecular pathogenesis. Blood, 87, 1211- 1224.
[56]	Raimondi, S.C., Privitera, E., Williams, D.L., Look, A.T., Behm, F., Rivera, G.K., et al. (1991) New recurring chromosomal translocations in childhood acute lymphoblastic leukemia. Blood, 77, 2016-2022.
[57]	Rubnitz, J.E., Behm, F.G., Curcio-Brint, A.M., Pinheiro, R.P., Carroll, A.J., Raimondi, S.C., et al. (1996) Molecular analysis of t(11;19) breakpoints in childhood acute leukemias. Blood, 87, 4804-4808.
[58]	Meyer, C., Schneider, B., Jakob, S., Strehl, S., Attarbaschi, A., Schnittger, S., et al. (2006) The MLL recombinome of acute leukemias. Leukemia, 20, 777-784. doi:10.1038/sj.leu.2404150