A Validated FISH Trisomy Index Demonstrates the Hyperdiploid and Nonhyperdiploid Dichotomy in MGUS

Overview

Journal Blood

Publisher Elsevier

Specialty Hematology

Date 2005 May 28

PMID 15920009

Citations 37

Authors

Wee Joo Chng

Scott A Van Wier

Gregory J Ahmann

Jerry M Winkler

Syed M Jalal

Peter Leif Bergsagel

Marta Chesi

Mike C Trendle

Martin M Oken

Emily Blood

Kim Henderson

Rafael Santana-Davila

Robert A Kyle

Morie A Gertz

Martha Q Lacy

Angela Dispenzieri

Philip R Greipp

Rafael Fonseca

Affiliations

Soon will be listed here.

Abstract

Two major genetic categories of multiple myeloma (MM) exist. Hyperdiploid MM (48 to 74 chromosomes, median 53 chromosomes) is associated with trisomies especially of chromosomes 3, 7, 9, 11, 15, and 19, whereas the nonhyperdiploid (< 48 chromosomes or more than 74 chromosomes) MM is associated with primary translocations such as t(11;14), t(4;14), and t(14;16). Whether this dichotomy exists in monoclonal gammopathy of undetermined significance (MGUS) is uncertain due to limitations of current methods in the study of ploidy. This is especially true in MGUS where the number of clonal plasma cells is small. In this study, we derived a fluorescent in situ hybridization (FISH)-based trisomy index from pooled cytogenetic data (karyotype analysis) from 2 large cohorts of patients with MM with abnormal karyotype, and then validated it in 2 independent cohorts of patients who had known ploidy status either by karyotyping or DNA content measurement using flow cytometry. Using the criteria of 2 or more trisomies from a 3-chromosome combination, hyperdiploid myeloma can be detected with high specificity. Applying this index on 28 patients with smoldering multiple myeloma (SMM) or MGUS (11 SMM, 17 MGUS) who had normal karyotype, 11 cases of hyperdiploid SMM/MGUS were detected. This percentage (40%) is remarkably similar to the percentage of hyperdiploid MM reported in the literature, suggesting that hyperdiploid MM may originate early during disease evolution.

Citing Articles

Monoclonal gammopathy of undetermined significance: evaluation, risk assessment, management, and beyond.

Abeykoon J, Tawfiq R, Kumar S, Ansell S Fac Rev. 2022; 11:34.

PMID: 36532706 PMC: 9720897. DOI: 10.12703/r/11-34.

A Comprehensive Review of the Genomics of Multiple Myeloma: Evolutionary Trajectories, Gene Expression Profiling, and Emerging Therapeutics.

Awada H, Thapa B, Awada H, Dong J, Gurnari C, Hari P Cells. 2021; 10(8).

PMID: 34440730 PMC: 8391934. DOI: 10.3390/cells10081961.

Epidemiology, genetics and treatment of multiple myeloma and precursor diseases.

Hemminki K, Forsti A, Houlston R, Sud A Int J Cancer. 2021; 149(12):1980-1996.

PMID: 34398972 PMC: 11497332. DOI: 10.1002/ijc.33762.

Genetic pathogenesis of immunoglobulin light chain amyloidosis: basic characteristics and clinical applications.

Xu L, Su Y Exp Hematol Oncol. 2021; 10(1):43.

PMID: 34284823 PMC: 8290569. DOI: 10.1186/s40164-021-00236-z.

Genetic Abnormalities in Multiple Myeloma: Prognostic and Therapeutic Implications.

Cardona-Benavides I, de Ramon C, Gutierrez N Cells. 2021; 10(2).

PMID: 33562668 PMC: 7914805. DOI: 10.3390/cells10020336.

References

Konigsberg R, Ackermann J, Kaufmann H, Zojer N, Urbauer E, Kromer E . Deletions of chromosome 13q in monoclonal gammopathy of undetermined significance. Leukemia. 2000; 14(11):1975-9. DOI: 10.1038/sj.leu.2401909. View

Zandecki M, Lai J, Genevieve F, Bernardi F, Blanchet O, Francois M . Several cytogenetic subclones may be identified within plasma cells from patients with monoclonal gammopathy of undetermined significance, both at diagnosis and during the indolent course of this condition. Blood. 1997; 90(9):3682-90. View

Ahmann G, Jalal S, Juneau A, Christensen E, Hanson C, Dewald G . A novel three-color, clone-specific fluorescence in situ hybridization procedure for monoclonal gammopathies. Cancer Genet Cytogenet. 1998; 101(1):7-11. DOI: 10.1016/s0165-4608(97)00058-7. View

Seong C, Delasalle K, Hayes K, Weber D, Dimopoulos M, Swantkowski J . Prognostic value of cytogenetics in multiple myeloma. Br J Haematol. 1998; 101(1):189-94. DOI: 10.1046/j.1365-2141.1998.00657.x. View

Smadja N, Fruchart C, Isnard F, Louvet C, Dutel J, Cheron N . Chromosomal analysis in multiple myeloma: cytogenetic evidence of two different diseases. Leukemia. 1998; 12(6):960-9. DOI: 10.1038/sj.leu.2401041. View

Almeida J, Orfao A, Mateo G, Ocqueteau M, Garcia-Sanz R, Moro M . Immunophenotypic and DNA content characteristics of plasma cells in multiple myeloma and monoclonal gammopathy of undetermined significance. Pathol Biol (Paris). 1999; 47(2):119-27. View

Avet-Loiseau H, Facon T, Daviet A, Godon C, Rapp M, Harousseau J . 14q32 translocations and monosomy 13 observed in monoclonal gammopathy of undetermined significance delineate a multistep process for the oncogenesis of multiple myeloma. Intergroupe Francophone du Myélome. Cancer Res. 1999; 59(18):4546-50. View

Oken M, Leong T, LENHARD Jr R, Greipp P, Kay N, Van Ness B . The addition of interferon or high dose cyclophosphamide to standard chemotherapy in the treatment of patients with multiple myeloma: phase III Eastern Cooperative Oncology Group Clinical Trial EST 9486. Cancer. 1999; 86(6):957-68. View

Greipp P, Trendle M, Leong T, Oken M, Kay N, Van Ness B . Is flow cytometric DNA content hypodiploidy prognostic in multiple myeloma?. Leuk Lymphoma. 1999; 35(1-2):83-9. DOI: 10.3109/10428199909145707. View

10.

Avet-Loiseau H, Li J, Morineau N, Facon T, Brigaudeau C, Harousseau J . Monosomy 13 is associated with the transition of monoclonal gammopathy of undetermined significance to multiple myeloma. Intergroupe Francophone du Myélome. Blood. 1999; 94(8):2583-9. View

11.

Rasmussen T, Kuehl M, Lodahl M, Johnsen H, Dahl I . Possible roles for activating RAS mutations in the MGUS to MM transition and in the intramedullary to extramedullary transition in some plasma cell tumors. Blood. 2004; 105(1):317-23. DOI: 10.1182/blood-2004-03-0833. View

12.

Uchida T, Kinoshita T, Ohno T, Ohashi H, Nagai H, Saito H . Hypermethylation of p16INK4A gene promoter during the progression of plasma cell dyscrasia. Leukemia. 2001; 15(1):157-65. DOI: 10.1038/sj.leu.2401991. View

13.

Smadja N, Bastard C, Brigaudeau C, Leroux D, Fruchart C . Hypodiploidy is a major prognostic factor in multiple myeloma. Blood. 2001; 98(7):2229-38. DOI: 10.1182/blood.v98.7.2229. View

14.

Kyle R, Therneau T, Rajkumar S, Offord J, Larson D, Plevak M . A long-term study of prognosis in monoclonal gammopathy of undetermined significance. N Engl J Med. 2002; 346(8):564-9. DOI: 10.1056/NEJMoa01133202. View

15.

Zhan F, Hardin J, Kordsmeier B, Bumm K, Zheng M, Tian E . Global gene expression profiling of multiple myeloma, monoclonal gammopathy of undetermined significance, and normal bone marrow plasma cells. Blood. 2002; 99(5):1745-57. DOI: 10.1182/blood.v99.5.1745. View

16.

Fonseca R, Bailey R, Ahmann G, Rajkumar S, Hoyer J, Lust J . Genomic abnormalities in monoclonal gammopathy of undetermined significance. Blood. 2002; 100(4):1417-24. View

17.

Rasillo A, Tabernero M, Sanchez M, Perez de Andres M, Martin Ayuso M, Hernandez J . Fluorescence in situ hybridization analysis of aneuploidization patterns in monoclonal gammopathy of undetermined significance versus multiple myeloma and plasma cell leukemia. Cancer. 2003; 97(3):601-9. DOI: 10.1002/cncr.11100. View

18.

Debes-Marun C, Dewald G, Bryant S, Picken E, Santana-Davila R, Gonzalez-Paz N . Chromosome abnormalities clustering and its implications for pathogenesis and prognosis in myeloma. Leukemia. 2003; 17(2):427-36. DOI: 10.1038/sj.leu.2402797. View

19.

Nilsson T, Hoglund M, Lenhoff S, Rylander L, Turesson I, Westin J . A pooled analysis of karyotypic patterns, breakpoints and imbalances in 783 cytogenetically abnormal multiple myelomas reveals frequently involved chromosome segments as well as significant age- and sex-related differences. Br J Haematol. 2003; 120(6):960-9. DOI: 10.1046/j.1365-2141.2003.04221.x. View

20.

Tucci A, Bonadonna S, Cattaneo C, Ungari M, Giustina A, Guiseppe R . Transformation of a MGUS to overt multiple myeloma: the possible role of a pituitary macroadenoma secreting high levels of insulin-like growth factor 1 (IGF-1). Leuk Lymphoma. 2003; 44(3):543-5. DOI: 10.1080/1042819021000037895. View