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Multiple myeloma in 2004

Written1998-01Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
Updated2004-06Franck Viguié
Laboratoire de Cytogenetique - Service d'Hematologie Biologique, Hopital Hotel-Dieu - 75181 Paris Cedex 04, France

(Note : for Links provided by Atlas : click)

Identity

ICD-Topo C420,C421,C424 BLOOD, BONE MARROW, & HEMATOPOIETIC SYS
ICD-Morpho 9732/3 Plasma cell myeloma / Multiple myeloma
Atlas_Id 2038

Clinics and Pathology

Disease multiple myeloma (MM) is a malignant monoclonal plasma cell proliferation. Monoclonal gammopathy of unknown significance (MGUS) and smoldering myeloma (SMM) are premalignant states susceptible to transform in MM
Phenotype / cell stem origin phenotype of mature terminally differenciated B-cell, but also with CD56 expression, which is not found in normal plasma cells; CD138+.CD38+ CD40+
Epidemiology multiple myeloma's annual incidence: 30/106; i.e. around 1% of malignancies in adults and 10% of haematologic malignancies; mean age: 62 yrs
Clinics patients may be asymptomatic at the time of diagnosis; bone pain; susceptibility to infections; renal failure; neurologic dysfunctions
Pathology MM staging: stage I: tumour cell mass < 0.6 X 1012/m2; Hb> 10 g/dl; serum calcium ¾ 120 mg/l; no bone lesion; low monoclonal Ig rate (IgG < 50 g/l, IgA < 30 g/l, BJ urine < 4 g/day); stage II: fitting neither stage I nor stage II; stage III: tumour cell mass > 1.2 X 1012/m2; Hb< 8.5 g/dl and/or serum calcium > 120 mg/l and/or advanced lytic bone lesions and/or high monoclonal Ig rate (IgG > 70 g/l, IgA > 50 g/l, BJ urine > 12 g/day)
Treatment none before onset of symptoms; chemotherapy or BMT afterwards. Various new therapies, mainly acting by apoptosis induction in MM cells, are or will be involved in clinical trails (thalidomide, proteasome inhibitor PS-341, 2 methoxy estradiol, arsenic trioxyde, TNF alpha).
Prognosis evolution: multiple myeloma can evolve towards plasma cell leukemia, where plasma cell count is greater than 2000/ mm3; survival is highly variable (median is around 3 yrs); prognosis is according to the staging and other parameters (such as age, serum albumin, b2 microglobulin, C-reactive protein, and plasma cell labeling index); the karyotype is emerging as an important prognostic factor: median survival in case of a normal karyotype could be 4 yrs vs 1 yr in case of -13/del(13q) and/or 11q rearrangements (the chromosome anomalies with the worst prognostic impact)

Cytogenetics

Cytogenetics Morphological cytogenetic information is limited, as the malignant cells have a low spontaneous proliferative activity; abnormal karyotypes are found in 30-50% of cases, more often in advanced stages than in newly diagnosed patients (is this because chromosome abnormalities are secondary events, or because malignant cells have an increased proliferative activity in advanced stages: see below); karyotypes are complex; hyperploidy is found in 2/3 of cases; karyotypes may evolve from normal to abnormal during course of the disease;
- structural (and variable) anomalies of chromosome 1 are found in 30-40% of cases, 14q rearrangements in 25% of cases, 11q abnormalities in 20 %, t(11;14)(q13;q32) representing 10%; 6q anomalies represent 15% of cases; FISH is indicated, as metaphases are arduous to obtain in such a disease implicating mature cells, and tend to show that most cases bear chromosome anomalies, irrespective of the disease staging.
Cytogenetics Molecular All MM cells should express chromosome abnormalities, as strongly suggested by interphase FISH and CGH.
Aneuploidy is detected in 67-90% of cases, allowing to define 2 prognosis entities:
1) hyperdiploid sub-group with a significantly better overall survival, gains involving primarily +3, +5, +7, +9, +11, +15, +19, +21 and infrequent structural abnormalities.
2) hypodiploid group (+hypotetraploid cases by endoreduplication of a prior hypodiploid karyotype) strongly correlated with complex structural rearrangements, 14q32 translocations, del(13q)/-13 and a more aggressive evolution.
IG rearrangements: translocations involving 14q32 are found in at least 65-70% of patients, most of them result from short segments exchange and are detected quite exclusively by FISH. Five translocations involving IGH locus are particularly relevant and considered as very early primary events: t(4;14)(p16;q32), t(6;14)(p25;q32), t(11;14)(q13;q32), t(14;16)(q32;q23), t(14;20)(q32;q11). Other translocations involving IGH are rare or sporadic, they should be secondary and not mediated by specific recombination mechanisms.
Del13q/-13: 13q14.3 deletions emerge as a major independant pronostic factor, underevaluated by conventional cytogenetics; found by FISH in 20-30% of patients; associated with a significant lower rate of response to conventional chemotherapy, and to a shorter survival.

Genes involved and Proteins

Gene Name FGFR3
Location 4p16
Note Involved in t(4;14)(p16;q32), approximately 15% of MM cases. FGFR3 (tyrosine kinase receptor) and MMSET (novel gene homologous to a Drosophila dysmorphy gene, see below)) are in opposite transcriptional orientation at 4p16. Both are involved in t(4;14). The translocation generates 2 fusion genes, IGH-MMSET on der(4) and FGFR3-IGH on der(14).
Gene Name WHSC1
Location 4p16
Note involved in t(4;14)(p16;q32) (see above)
Gene Name CCND3
Location 6p21
Note Involved in t(6;14)(p21;q32) (3-5% of MM cases). Detected quasi exclusively by FISH.
Gene Name CCND1
Location 11q13
Note BCL1 (also called Cyclin D1 or CCND1) is involved in t(11;14) )(q13;q32) cases. Approximately 15-20% of cases. Same translocation as mantle cell lymphoma but IGH breakpoint different (IGHS vs IGHJ)
Gene Name MAF
Location 16q23
Note basic zipper transcription factor, involved in t(14;16)(q32;q23) (5% of MM cases). Detected quasi exclusively by FISH
Gene Name MAFB
Location 20q11
Note MAF family basic region / leucine zipper transcription factor, involved in t(14;20)(q32;q11) (2% of MM cases)

Bibliography

Cytogenetic analysis of 280 patients with multiple myeloma and related disorders: primary breakpoints and clinical correlations.
Calasanz MJ, Cigudosa JC, Odero MD, Ferreira C, Ardanaz MT, Fraile A, Carrasco JL, Solé F, Cuesta B, Gullón A
Genes, chromosomes & cancer. 1997 ; 18 (2) : 84-93.
PMID 9115968
 
Cytogenetics and molecular genetics in multiple myeloma.
Feinman R, Sawyer J, Hardin J, Tricot G
Hematology/oncology clinics of North America. 1997 ; 11 (1) : 1-25.
PMID 9081201
 
Genetics and cytogenetics of multiple myeloma: a workshop report.
Fonseca R, Barlogie B, Bataille R, Bastard C, Bergsagel PL, Chesi M, Davies FE, Drach J, Greipp PR, Kirsch IR, Kuehl WM, Hernandez JM, Minvielle S, Pilarski LM, Shaughnessy JD Jr, Stewart AK, Avet-Loiseau H
Cancer research. 2004 ; 64 (4) : 1546-1558.
PMID 14989251
 
Cytogenetics of multiple myeloma: interpretation of fluorescence in situ hybridization results.
Harrison CJ, Mazzullo H, Cheung KL, Gerrard G, Jalali GR, Mehta A, Osier DG, Orchard KH
British journal of haematology. 2003 ; 120 (6) : 944-952.
PMID 12648063
 
Advances in biology of multiple myeloma: clinical applications.
Hideshima T, Bergsagel PL, Kuehl WM, Anderson KC
Blood. 2004 ; 104 (3) : 607-618.
PMID 15090448
 
Multiple myeloma and chronic lymphocytic leukemia.
Rosen L, Vescio R, Berenson JR
Current opinion in hematology. 1995 ; 2 (4) : 275-282.
PMID 9372008
 
Hypodiploidy is a major prognostic factor in multiple myeloma.
Smadja NV, Bastard C, Brigaudeau C, Leroux D, Groupe Français de Cytogénétique Hématologique (GFCH).
Blood. 2001 ; 98 (7) : 2229-2238.
PMID 11568011
 

Citation

This paper should be referenced as such :
Viguié, F
Multiple myeloma
Atlas Genet Cytogenet Oncol Haematol. 2004;8(3):245-247.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Anomalies/MMULID2038.html
History of this paper:
Huret, JL. Multiple myeloma. Atlas Genet Cytogenet Oncol Haematol. 1998;2(1):18-19.
http://documents.irevues.inist.fr/bitstream/handle/2042/32102/01-1998-MMULID2038.pdf


Other genes implicated (Data extracted from papers in the Atlas) [ 88 ]

Genes ADAM23 AKT1 ANKHD1 AURKA CCND1 CCND1 CCND1 BCL6 BIRC2 BMP4
BNIP3L TIGAR CCR1 CCR2 CD200 CD38 CD74 CHST11 CKS1B CUX1
CYLD DKK1 DUSP6 ENG ENO1 FAS FGF2 FGFR3 GLI2 GRN
HFE HLA-G HSPB1 IGH IGH IL21R IL23A IL6 ING1 ING4
INPPL1 IRF4 JAG2 KDR MVP MAFA MAFB MAF MAGEA3 MAPKAPK2
MIB2 MIR744 ABCC1 MYC MYEOV NFKB2 NOTCH1 NR3C1 ORAI3 PASD1
PF4 PIK3CD PLAUR PRDM1 PTGS2 PTN RANBP2 RAN RUNX2 SDC1
SGK1 SMYD3 SOCS1 SPA17 SSX2 STMN1 SULF1 TACC3 TFRC TGFBR3
TNFRSF17 TPD52 TRIAP1 TXN TYRO3 NSD2 XAF1 YBX1

External links

COSMICHisto = - Site = haematopoietic_and_lymphoid_tissue (COSMIC)
arrayMapTopo ( C42) Morph ( 9732/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
 
 
Other databaseTumor Portal - Broad Institute
Other databasecBioPortal: Multiple Myeloma (Broad, Cancer Cell 2014)
Other databaseMultiple myeloma ( intOGen )
Other databaseMultiple Myeloma Overview - Disease Synopsis [canSAR]
Disease databaseMultiple myeloma in 2004
REVIEW articlesautomatic search in PubMed
Last year articlesautomatic search in PubMed
All articlesautomatic search in PubMed


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indexed on : Tue Mar 14 13:54:06 CET 2017


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