Characteristic recurrent copy number aberrations (CNAs) play a key role in multiple myeloma (MM) pathogenesis and have important prognostic significance for MM patients. Array-based comparative genomic hybridization (aCGH) provides a powerful tool for genome-wide classification of CNAs and thus should be implemented into MM routine diagnostics. We demonstrate the possibility of effective utilization of oligonucleotide-based aCGH in 91 MM patients. Chromosomal aberrations associated with effect on the prognosis of MM were initially evaluated by I-FISH and were found in 93.4% (85/91). Incidence of hyperdiploidy was 49.5% (45/91); del(13)(q14) was detected in 57.1% (52/91); gain(1)(q21) occurred in 58.2% (53/91); del(17)(p13) was observed in 15.4% (14/91); and t(4;14)(p16;q32) was found in 18.6% (16/86). Genome-wide screening using Agilent 44K aCGH microarrays revealed copy number alterations in 100% (91/91). Most common deletions were found at 13q (58.9%), 1p (39.6%), and 8p (31.1%), whereas gain of whole 1q was the most often duplicated region (50.6%). Furthermore, frequent homozygous deletions of genes playing important role in myeloma biology such as TRAF3, BIRC1/BIRC2, RB1, or CDKN2C were observed. Taken together, we demonstrated the utilization of aCGH technique in clinical diagnostics as powerful tool for identification of unbalanced genomic abnormalities with prognostic significance for MM patients.

Babak Myeloma Group Department of Pathological Physiology Faculty of Medicine Masaryk University Brno Bohunice 62500 Brno Czech Republic

Babak Myeloma Group Department of Pathological Physiology Faculty of Medicine Masaryk University Brno Bohunice 62500 Brno Czech Republic ; Department of Internal Hematooncology University Hospital Brno Bohunice 62500 Brno Czech Republic

Babak Myeloma Group Department of Pathological Physiology Faculty of Medicine Masaryk University Brno Bohunice 62500 Brno Czech Republic ; Department of Internal Hematooncology University Hospital Brno Bohunice 62500 Brno Czech Republic ; Faculty of Medicine University of Ostrava and University Hospital Ostrava Poruba 70852 Ostrava Czech Republic

Department of Clinical Hematology University Hospital Brno Bohunice 62500 Brno Czech Republic

Department of Experimental Biology Faculty of Science Masaryk University Brno Bohunice 62500 Brno Czech Republic

Department of Experimental Biology Faculty of Science Masaryk University Brno Bohunice 62500 Brno Czech Republic ; Babak Myeloma Group Department of Pathological Physiology Faculty of Medicine Masaryk University Brno Bohunice 62500 Brno Czech Republic

Faculty of Medicine University of Ostrava and University Hospital Ostrava Poruba 70852 Ostrava Czech Republic

Zobrazit více v PubMed

Dimopoulos M, Kyle R, Fermand J-P, et al. Consensus recommendations for standard investigative workup: report of the International Myeloma Workshop Consensus Panel 3. Blood. 2011;117(18):4701–4705. PubMed

Fonseca R, Barlogie B, Bataille R, et al. Genetics and cytogenetics of multiple myeloma: a workshop report. Cancer Research. 2004;64(4):1546–1558. PubMed

Fonseca R, Harrington D, Oken MM, et al. Biological and prognostic significance of interphase fluorescence in situ hybridization detection of chromosome 13 abnormalities (Δ13) in multiple myeloma: an Eastern Cooperative Oncology Group study. Cancer Research. 2002;62(3):715–720. PubMed

Smadja NV, Bastard C, Brigaudeau C, Leroux D, Fruchart C. Hypodiploidy is a major prognostic factor in multiple myeloma. Blood. 2001;98(7):2229–2238. PubMed

Shaughnessy J. Amplification and overexpression of CKS1B at chromosome band 1q21 is associated with reduced levels of p27 Kip1 and an aggressive clinical course in multiple myeloma. Hematology. 2005;10(1):117–126. PubMed

Fonseca R, Van Wier SA, Chng WJ, et al. Prognostic value of chromosome 1q21 gain by fluorescent in situ hybridization and increase CKS1B expression in myeloma. Leukemia. 2006;20(11):2034–2040. PubMed

Gutiérrez NC, García JL, Hernández JM, et al. Prognostic and biologic significance of chromosomal imbalances assessed by comparative genomic hybridization in multiple myeloma. Blood. 2004;104(9):2661–2666. PubMed

Walker BA, Morgan GJ. Use of single nucleotide polymorphism—based mapping arrays to detect copy number changes and loss of heterozygosity in multiple myeloma. Clinical Lymphoma and Myeloma. 2006;7(3):186–191. PubMed

Largo C, Alvarez S, Saez B, et al. Identification of overexpressed genes in frequently gained/amplified chromosome regions in multiple myeloma. Haematologica. 2006;91(2):184–191. PubMed

Chapman MA, Lawrence MS, Keats JJ, et al. Initial genome sequencing and analysis of multiple myeloma. Nature. 2011;471(7339):467–472. PubMed PMC

Nemec P, Zemanova Z, Kuglik P, et al. Complex karyotype and translocation t(4;14) define patients with high-risk newly diagnosed multiple myeloma: results of CMG2002 trial. Leukemia and Lymphoma. 2012;53(5):920–927. PubMed

Greslikova H, Zaoralova R, Filkova H, et al. Negative prognostic significance of two or more cytogenetic abnormalities in multiple myeloma patients treated with autologous stem cell transplantation. Neoplasma. 2010;57(2):111–117. PubMed

Cumova J, Kovarova L, Potacova A, et al. Optimization of immunomagnetic selection of myeloma cells from bone marrow using magnetic activated cell sorting. International Journal of Hematology. 2010;92(2):314–319. PubMed

Smetana J, Fröhlich J, Vranová V, Mikulášová A, Kuglík P, Hájek R. Oligonucleotide-based array CGH as a diagnostic tool in multiple myeloma patients. Klinicka Onkologie. 2011;24:S43–S48. PubMed

Lipson D, Aumann Y, Ben-Dor A, Linial N, Yakhini Z. Efficient calculation of interval scores for DNA copy number data analysis. Journal of Computational Biology. 2006;13(2):215–228. PubMed

Ahmann GJ, Jalal SM, Juneau AL, et al. A novel three-color, clone-specific fluorescence in situ hybridization procedure for monoclonal gammopathies. Cancer Genetics and Cytogenetics. 1998;101(1):7–11. PubMed

Ross FM, Avet-Loiseau H, Ameye G, et al. Report from the European myeloma network on interphase FISH in multiple myeloma and related disorders. Haematologica. 2012;97(8):1272–1277. PubMed PMC

Kumar S, Fonseca R, Ketterling RP, et al. Trisomies in multiple myeloma: impact on survival in patients with high-risk cytogenetics. Blood. 2012;119(9):2100–2105. PubMed PMC

Fonseca R, Bergsagel PL, Drach J, et al. International Myeloma Working Group molecular classification of multiple myeloma: spotlight review. Leukemia. 2009;23(12):2210–2221. PubMed PMC

Gutiérrez NC, Castellanos MV, Martín ML, et al. Prognostic and biological implications of genetic abnormalities in multiple myeloma undergoing autologous stem cell transplantation: t(4;14) is the most relevant adverse prognostic factor, whereas RB deletion as a unique abnormality is not associated with adverse prognosis. Leukemia. 2007;21(1):143–150. PubMed

Lodé L, Eveillard M, Trichet V, et al. Mutations in TP53 are exclusively associated with del(17p) in multiple myeloma. Haematologica. 2010;95(11):1973–1976. PubMed PMC

Smetana J, Berankova K, Zaoralova R, et al. Gain(1)(q21) is an unfavorable genetic prognostic factor for patients with relapsed multiple myeloma treated with thalidomide but not for those treated with bortezomib. Clinical Lymphoma, Myeloma and Leukemia. 2013;13(2):123–130. PubMed

Carrasco DR, Tonon G, Huang Y, et al. High-resolution genomic profiles define distinct clinico-pathogenetic subgroups of multiple myeloma patients. Cancer Cell. 2006;9(4):313–325. PubMed

Avet-Loiseau H, Li C, Magrangeas F, et al. Prognostic significance of copy-number alterations in multiple myeloma. Journal of Clinical Oncology. 2009;27(27):4585–4590. PubMed PMC

Boyd KD, Ross FM, Walker BA, et al. Mapping of chromosome 1p deletions in myeloma identifies FAM46C at 1p12 and CDKN2C at 1p32.3 as being genes in regions associated with adverse survival. Clinical Cancer Research. 2011;17(24):7776–7784. PubMed PMC

Walker BA, Leone PE, Chiecchio L, et al. A compendium of myeloma-associated chromosomal copy number abnormalities and their prognostic value. Blood. 2010;116(15):e56–e65. PubMed

Chang H, Qi X, Jiang A, Xu W, Young T, Reece D. 1p21 deletions are strongly associated with 1q21 gains and are an independent adverse prognostic factor for the outcome of high-dose chemotherapy in patients with multiple myeloma. Bone Marrow Transplantation. 2010;45(1):117–121. PubMed

Boyd KD, Ross FM, Tapper WJ, et al. The clinical impact and molecular biology of del(17p) in multiple myeloma treated with conventional or thalidomide-based therapy. Genes Chromosomes and Cancer. 2011;50(10):765–774. PubMed

Demchenko YN, Glebov OK, Zingone A, Keats JJ, Leif Bergsagel P, Michael Kuehl W. Classical and/or alternative NF-κB pathway activation in multiple myeloma. Blood. 2010;115(17):3541–3552. PubMed PMC

Keats JJ, Fonseca R, Chesi M, et al. Promiscuous mutations activate the noncanonical NF-κB pathway in multiple myeloma. Cancer Cell. 2007;12(2):131–144. PubMed PMC

Braggio E, Keats JJ, Leleu X, et al. Identification of copy number abnormalities and inactivating mutations in two negative regulators of nuclear factor-κB signaling pathways in Waldenström’s macroglobulinemia. Cancer Research. 2009;69(8):3579–3588. PubMed PMC

Dickens NJ, Walker BA, Leone PE, et al. Homozygous deletion mapping in myeloma samples identifies genes and an expression signature relevant to pathogenesis and outcome. Clinical Cancer Research. 2010;16(6):1856–1864. PubMed PMC

Gardam S, Turner VM, Anderton H, et al. Deletion of cIAP1 and cIAP2 in murine B lymphocytes constitutively activates cell survival pathways and inactivates the germinal center response. Blood. 2011;117(15):4041–4051. PubMed

Di Fiore R, D’Anneo A, Tesoriere G, Vento R. RB1 in cancer: different mechanisms of RB1 inactivation and alterations of pRb pathway in tumorigenesis. Journal of Cellular Physiology. 2013;228(8):1676–1687. PubMed

Gunn SR, Mohammed MS, Gorre ME, et al. Whole-genome scanning by array comparative genomic hybridization as a clinical tool for risk assessment in chronic lymphocytic leukemia. Journal of Molecular Diagnostics. 2008;10(5):442–451. PubMed PMC

Tyybäkinoja A, Vilpo J, Knuutila S. High-resolution oligonucleotide array-CGH pinpoints genes involved in cryptic losses in chronic lymphocytic leukemia. Cytogenetic and Genome Research. 2007;118(1):8–12. PubMed

Patel A, Kang S-H, Lennon PA, et al. Validation of a targeted DNA microarray for the clinical evaluation of recurrent abnormalities in chronic lymphocytic leukemia. American Journal of Hematology. 2008;83(7):540–546. PubMed

O’Malley DP, Giudice C, Chang AS, et al. Comparison of array comparative genomic hybridization (aCGH) to FISH and cytogenetics in prognostic evaluation of chronic lymphocytic leukemia. International Journal of Laboratory Hematology. 2011;33(3):238–244. PubMed

Largo C, Saéz B, Alvarez S, et al. Multiple myeloma primary cells show a highly rearranged unbalanced genome with amplifications and homozygous deletions irrespective of the presence of immunoglobulin-related chromosome translocations. Haematologica. 2007;92(6):795–802. PubMed

Valli R, Maserati E, Marletta C, Pressato B, Lo Curto F, Pasquali F. Evaluating chromosomal mosaicism by array comparative genomic hybridization in hematological malignancies: the proposal of a formula. Cancer Genetics. 2011;204(4):216–218. PubMed

Chromothripsis 18 in multiple myeloma patient with rapid extramedullary relapse

The spectrum of somatic mutations in monoclonal gammopathy of undetermined significance indicates a less complex genomic landscape than that in multiple myeloma