Abstract
The nonrandom recurrent nature of chromosome abnormalities in myeloma suggests a role for them in disease pathogenesis. We performed a careful cytogenetic analysis of patients with abnormal karyotypes (n = 254), to discern patterns of association, search for novel abnormalities and elucidate clinical implications. Patients with karyotypic abnormalities suggestive of myelodysplasia/acute leukemia were excluded. In this study we compared survival by abnormality only between patients with abnormal karyotypes. Patients with abnormalities were more likely to have features of aggressive disease as compared to all other patients without abnormalities entered into the myeloma database (lower hemoglobin, higher β2-microglobulin, labeling-index and plasmocytosis; all P < 0.0001). Several groups of patients could be readily identified; hypodiploid (22%), pseudodiploid (36%), hyperdiploid (31%) and near-tetraploid (11%). Clustering associations were seen among several trisomies and monosomy of chromosome 13 and 14. Several monosomies (−2, −3, −13, −14 and −19), 1p translocations/ deletions, and hypodiploidy were associated with a significantly shorter survival. Trisomy of chromosome 13 was rare (<2%). Even among patients with abnormal karyotypes, specific chromosome abnormalities can impart biologic variability in myeloma, including several monosomies, hypodiploidy and abnormalities of 1p.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Zandecki M . Multiple-myeloma – almost all patients are cytogenetically abnormal. Br J Haematol 1996; 94: 217–227.
Hallek M, Leif Bergsagel P, Anderson KC . Multiple myeloma: increasing evidence for a multistep transformation process. Blood 1998; 91: 3–21.
Dewald GW, Kyle RA, Hicks GA, Greipp PR . The clinical significance of cytogenetic studies in 100 patients with multiple myeloma, plasma cell leukemia, or amyloidosis. Blood 1985; 66: 380–390.
Sawyer JR, Lukacs JL, Thomas EL, Swanson CM, Goosen LS, Sammartino G, Gilliland JC, Munshi NC, Tricot G, Shaughnessy JD Jr Barlogie B . Multicolour spectral karyotyping identifies new translocations and a recurring pathway for chromosome loss in multiple myeloma. Br J Haematol 2001; 112: 167–174.
Calasanz MJ, Cigudosa JC, Odero MD, Ferreira C, Ardanaz MT, Fraile A, Carrasco JL, Sole F, Cuesta B, Gullon A . Cytogenetic analysis of 280 patients with multiple myeloma and related disorders: primary breakpoints and clinical correlations. Genes Chromos Cancer 1997; 18: 84–93.
Avet-Loiseau H, Daviet A, Brigaudeau C, Callet-Bauchu E, Terre C, Lafage-Pochitaloff M, Desangles F, Ramond S, Talmant P, Bataille R . Cytogenetic, interphase, and multicolor fluorescence in situ hybridization analyses in primary plasma cell leukemia: a study of 40 patients at diagnosis, on behalf of the Intergroupe Francophone du Myelome and the Groupe Français de Cytogenetique Hematologique. Blood 2001; 97: 822–825.
Sawyer JR, Waldron JA, Jagannath S, Barlogie B . Cytogenetic findings in 200 patients with multiple myeloma. Cancer Genet Cytogenet 1995; 82: 41–49.
Rajkumar SV, Fonseca R, Dewald GW, Therneau TM, Lacy MQ, Kyle RA, Greipp PR, Gertz MA . Cytogenetic abnormalities correlate with the plasma cell labeling index and extent of bone marrow involvement in myeloma. Cancer Genet Cytogenet 1999; 113: 73–77.
Fonseca R, Coignet LJ, Dewald GW . Cytogenetic abnormalities in multiple myeloma. Hematol Oncol Clin North Am 1999; 13: 1169–1180.
Avet-Loiseau H, Facon T, Grosbois B, Magrangeas F, Rapp M-J, Harousseau J-L, Minvielle S, Bataille R . Oncogenesis of multiple myeloma: 14q32 and 13q chromosomal abnormalities are not randomly distributed, but correlate with natural history, immunological features, and clinical presentation. Blood 2002; 99: 2185–2191.
Bergsagel PL, Chesi M, Nardini E, Brents LA, Kirby SL, Kuehl WM . Promiscuous translocations into immunoglobulin heavy chain switch regions in multiple myeloma. Proc Natl Acad Sci USA 1996; 93: 13931–13936.
Drach J, Angerler J, Schuster J, Thalhammer R, Jager U, Geissler R, Lechner R, Ludwig H, Huber H . Clonal chromosomal aberrations in plasma cells from patients with monoclonal gammopathy of undetermined significance (MGUS). Proc Annu Meet Am Assoc Cancer Res 1995; 36 (Abstr.).
Drach J, Angerler J, Schuster J, Rothermundt C, Thalhammer R, Haas OA, Jager U, Fiegl M, Geissler K, Ludwig H . Interphase fluorescence in situ hybridization identifies chromosomal abnormalities in plasma cells from patients with monoclonal gammopathy of undetermined significance. Blood 1995; 86: 3915–3921.
Fonseca R, Oken M, Harrington D, Bailey R, Van Wier S, Henderson K, Kay N, Van Ness B, Greipp P, Dewald G . Deletions of chromosome 13 in multiple myeloma identified by interphase FISH usually denote large deletions of the q-arm or monosomy. Leukemia 2001; 15: 981–986.
Sawyer JR, Tricot G, Mattox S, Jagannath S, Barlogie B . Jumping translocations of chromosome 1q in multiple myeloma: evidence for a mechanism involving decondensation of pericentromeric heterochromatin. Blood 1998; 91: 1732–1741.
Fonseca R, Dewald G, Coignet L . Cytogenetic abnormalities in multiple myeloma. Hematol Oncol Clin North Am 1999; 13: 1169–1180.
Tricot G, Sawyer JR, Jagannath S, Desikan KR, Siegel D, Naucke S, Mattox S, Bracy D, Munshi N, Barlogie B . Unique role of cytogenetics in the prognosis of patients with myeloma receiving high-dose therapy and autotransplants. J Clin Oncol 1997; 15: 2659–2666.
Zojer N, Konigsberg R, Ackermann J, Fritz E, Dallinger S, Kromer E, Kaufmann H, Riedl L, Gisslinger H, Schreiber S, Heinz R, Ludwig H, Huber H, Drach J . Deletion of 13q14 remains an independent adverse prognostic variable in multiple myeloma despite its frequent detection by interphase fluorescence in situ hybridization. Blood 2000; 95: 1925–1930.
Konigsberg R, Zojer N, Ackermann J, Kromer E, Kittler H, Fritz E, Kaufmann H, Nosslinger T, Riedl L, Gisslinger H, Jager U, Simonitsch I, Heinz R, Ludwig H, Huber H, Drach J . Predictive role of interphase cytogenetics for survival of patients with multiple myeloma. J Clin Oncol 2000; 18: 804–812.
Cox D . Analysis of Binary Data, Methuen: London 1970.
Wilcoxon F . Individual comparisons by ranking methods. Biometrics 1945; 1: 80–83.
Kaplan EL, Meier P . Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457–481.
Peto R, Peto J . Asymptotically efficient rank invariant test procedures. J Roy Stat Soc Ser A 1972; 135: 185–206.
Hartigan JA . Clustering Algorithms, John Wiley: New York 1975.
Smadja NV, Bastard C, Brigaudeau C, Leroux D, Fruchart C . Hypodiploidy is a major prognostic factor in multiple myeloma. Blood 2001; 98: 2229–2238.
Garcia-Sanz R, Orfao A, Gonzalez M, Moro MJ, Hernandez JM, Ortega F, Borrego D, Carnero M, Casanova F, Jimenez R, Portero JA, San Miguel JF . Prognostic implications of DNA aneuploidy in 156 untreated multiple myeloma patients. Castelano-Leones (Spain) Cooperative Group for the Study of Monoclonal Gammopathies. Br J Haematol 1995; 90: 106–112.
Seong C, Delasalle K, Hayes K, Weber D, Dimopoulos M, Swantkowski J, Huh Y, Glassman A, Champlin R, Alexanian R . Prognostic value of cytogenetics in multiple myeloma. Br J Haematol 1998; 101: 189–194.
Lai JL, Michaux L, Dastugue N, Vasseur F, Daudignon A, Facon T, Bauters F, Zandecki M . Cytogenetics in multiple myeloma – a multicenter study of 24 patients with t(11-14)(q13-q32) or its variant. Cancer Genet Cytogenet 1998; 104: 133–138.
Drach J, Schuster J, Nowotny H, Angerler J, Rosenthal F, Fiegl M, Rothermundt C, Gsur A, Jager U, Heinz R . Multiple myeloma: high incidence of chromosomal aneuploidy as detected by interphase fluorescence in situ hybridization. Cancer Res 1995; 55: 3854–3859.
Tabernero D, San Miguel JF, Garcia-Sanz M, Najera L, Garcia-Isidoro M, Perez-Simon JA, Gonzalez M, Wiegant J, Raap AK, Orfao A . Incidence of chromosome numerical changes in multiple myeloma: fluorescence in situ hybridization analysis using 15 chromosome-specific probes. Am J Pathol 1996; 149: 153–161.
Fonseca R, Ahmann GJ, Juneau AL, Jalal SM, Dewald GW, Larson DM, Therneau TM, Gertz MA, Greipp PR . Cytogenetic abnormalities in multiple myeloma and related plasma cell disorders: a comparison of conventional cytogenetic analysis to fluorescent in situ hybridization with simultaneous cytoplasmic immunoglobulin staining. Blood 1997; 90: 1558a 1349 (Abstr.).
Smith L, Barlogie B, Alexanian R . Biclonal and hypodiploid multiple myeloma. Am J Med 1986; 80: 841–843.
Calasanz MJ, Cigudosa JC, Odero MD, Garcia-Foncillas J, Marin J, Ardanaz MT, Rocha E, Gullon A . Hypodiploidy and 22q11 rearrangements at diagnosis are associated with poor prognosis in patients with multiple myeloma. Br J Haematol 1997; 98: 418–425.
Greipp PR, Trendle MC, Leong T, Oken MM, Kay NE, Van Ness B, Kyle RA . Is flow cytometric DNA content hypodiploidy prognostic in multiple myeloma?. Leuk Lymphoma 1999; 35: 83–89.
Perez-Simon JA, Garcia-Sanz R, Tabernero MD, Almeida J, Gonzalez M, Fernandez-Calvo J, Moro MJ, Hernandez JM, San Miguel JF, Orfao A . Prognostic value of numerical chromosome aberrations in multiple myeloma: a FISH analysis of 15 different chromosomes. Blood 1998; 91: 3366–3371.
Lai JL, Zandecki M, Mary JY, Bernardi F, Izydorczyk V, Flactif M, Morel P, Jouet JP, Bauters F, Facon T . Improved cytogenetics in multiple myeloma: a study of 151 patients including 117 patients at diagnosis. Blood 1995; 85: 2490–2497.
Fonseca R, Oken M, Greipp P . The t(4;14)(p16.3;q32) is strongly associated with chromosome 13 abnormalities (Δ13) in both multiple myeloma (MM) and MGUS. Blood 2001; 98: 1271–1272.
Avet-Loiseau H, Daviet A, Saunier S, Bataille R . Chromosome 13 abnormalities in multiple myeloma are mostly monosomy 13. Br J Haematol 2000; 111: 1116–1117.
Facon T, Avet-Loiseau H, Guillerm G, Moreau P, Geneviève F, Zandecki M, La? J, Leleu X, Jouet J, Bauters F, Harousseau J, Bataille R, Mary J . Chromosome 13 abnormalities identified by FISH analysis and serum beta-2-microglobulin produce a powerful myeloma staging system for patients receiving high-dose therapy. Blood 2001; 97: 1566–1571.
Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A, Boldrick JC, Sabet H, Tran T, Yu X, Powell JI, Yang L, Marti GE, Moore T, Hudson J Jr, Lu L, Lewis DB, Tibshirani R, Sherlock G, Chan WC, Greiner TC, Weisenburger DD, Armitage JO, Warnke R, Levy R, Wilson W, Grever MR, Byrd JC, Botstein D, Brown PO, Staudt LM . Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 2000; 403: 503–511.
Zhan F, Hardin J, Kordsmeier B, Bumm K, Zheng M, Tian E, Sanderson R, Yang Y, Wilson C, Zangari M, Anaissie E, Morris C, Muwalla F, van Rhee F, Fassas A, Crowley J, Tricot G, Barlogie B, Shaughnessy J Jr . Global gene expression profiling of multiple myeloma, monoclonal gammopathy of undetermined significance, and normal bone marrow plasma cells. Blood 2002; 99: 1745–1757.
Acknowledgements
RF is a Clinical Investigator of the Damon Runyon Cancer Research Fund and a Leukemia and Lymphoma Society Translational Research Awardee. This work was supported in part by Public Health Service grant no. R01 CA83724-01 (RF) and P01 CA62242 (RAK, PRG, TEW, JAL) from the National Cancer Institute, and the ‘Foundation to Cure Myeloma’ supports RF and PRG. PRG is supported by the ECOG grant CA21115-25C from the National Cancer Institute.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Debes-Marun, C., Dewald, G., Bryant, S. et al. Chromosome abnormalities clustering and its implications for pathogenesis and prognosis in myeloma. Leukemia 17, 427–436 (2003). https://doi.org/10.1038/sj.leu.2402797
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.leu.2402797
Keywords
This article is cited by
-
p21-Activated kinases as promising therapeutic targets in hematological malignancies
Leukemia (2022)
-
Plasma cell myeloma: role of histopathology, immunophenotyping, and genetic testing
Skeletal Radiology (2022)
-
Chromosome 1q21 abnormalities in multiple myeloma
Blood Cancer Journal (2021)
-
CNV Radar: an improved method for somatic copy number alteration characterization in oncology
BMC Bioinformatics (2020)
-
Risk Stratification in Multiple Myeloma in Indian Settings
Indian Journal of Hematology and Blood Transfusion (2020)