|
|
 Previous Article | Table of Contents | Next Article 
Blood, 15 August 2001, Vol. 98, No. 4, pp. 1271-1272
CORRESPONDENCE
To the editor:
The t(4;14)(p16.3;q32) is strongly associated with chromosome
13 abnormalities in both multiple myeloma and monoclonal gammopathy of
undetermined significance
We read with great interest the paper by Chesi et al
regarding FGFR3 that further supports the role of
FGFR3 in the pathogenesis of multiple myeloma
(MM).1 Monoclonal gammopathy of undetermined significance
(MGUS) also has genetic abnormalities seen in MM, including the
t(4;14)(p16.3;q32)2,3 with presumptive up-regulation of the
FGFR3 oncogene. Here we provide additional data attesting that the pathogenetic pathways in MM are highly specific. Specifically, we find that in MGUS and MM the t(4;14)(p16.3;q32) is strongly associated with  13. We tested 155 patients with MM and 52 patients with MGUS/SMM
(50 with MGUS and 2 with SMM) for evidence of the t(4;14)(p16.3;q32) using cIg-FISH with a fusion strategy for detection of the abnormality. For IgH locus we used the previously published probes by Gabrea et
al4 (VH and CH probes), and both
probes were directly labeled with SpectrumGreen (Vysis, Downers Grove,
IL). For the 4p16.3 locus, we used the PAC probe previously
used by Chesi et al5 (FGFR3 PAC184d6/385). We
also used a BAC clone containing sequences of the centromeric most
cosmid (96a2) in the contig described by Chesi et
al,6 retrieved with the PCR primers
5'-ACAAGACGCTACTGTTTTCC-3' and 5'-TCTAGATCTCTGCATCGAGC-3' and
purchased from Incyte Genomics (human BAC Release II; Palo Alto,
CA). Both 4p16.3 probes were directly labeled with SpectrumRed
(Vysis). A patient was considered to have the t(4;14)(p16.3;q32) if the
percent of abnormal plasma cells exceeded 10% of signals with an
abnormal pattern (fusions) indicative of a t(4;14)(p16.3;q32). All of
these patients were also tested for 13 by the previously published
strategy and methods using the probes LSI13-Rb and
D13S319.8 Of 155 MM patients, 16 (10.3%) had an abnormal pattern consistent with
the t(4;14)(p16.3;q32). The median percentage of abnormal plasma cells
(MPAPC) was 88% (range, 40%-100%). Fifteen of 16 MM patients (94%)
with the t(4;14)(p16.3;q32) had 13 (MPAPC 99%; range, 96%-100%).
Likewise, we found the t(4;14)(p16.3;q32) in a similar proportion, 5 (9.6%) of 52 patients with MGUS/SMM (3 MGUS, 1 SMM); (MPAPC 86%;
range, 49%-100%). In 3 of 4 (75%) patients with MGUS/SMM and the
t(4;14)(p16.3;q32), we found concurrent 13 (MPAPC 91%; 91%, 91%,
and 98%). The incidence of 13 in MGUS, SMM, and MM is strikingly
different from what we and others have previously reported in
MM7,8 (about 50%) and MGUS (about 30%).7 We believe this study provides important information regarding the
progression pathways from MGUS to MM. First, as previously mentioned,7 we have shown in MM a striking association of
the t(4;14)(p16.3;q32) with 13 in both MM and MGUS. This would
suggest that 13 is an important factor in the pathogenesis of
MGUS/MM with the t(4;14)(p16.3;q32) rather than being a factor
promoting progression from MGUS to MM. The near-obligate presence of
13 in MM with the t(4;14)(p16.3;q32), but not the opposite, suggests that 13 occurs prior to the translocation event. Because of the low
prevalence of ras mutations, the association with
FGFR3 mutations, and the striking associations with 13,
we postulate that MM with the t(4;14)(p16.3;q32) represents a unique
subtype of MM. We thus propose a refinement in the model, as shown in
Figure 1, that incorporates the
t(4;14)(p16.3;q32), 13, ras, and FGFR3
mutations. The results of this study also highlight the high likelihood
that subgroups of MGUS patients, classified according to the underlying genetic abnormalities, may be at different risk of progression to MM.
This is in need of a prospective study.
View larger version (17K):
[in this window]
[in a new window]
| Figure 1.
A modified model for progression of MGUS and MM with the
t(4;14)(p16.3;q32).
This modified version incorporates the presence of 13 since early in
the process of pathogenesis as a critical component of the
establishment of a malignant clone.
|
|
We thank the excellent technical assistance of S. Van Wier, R.J.
Bailey, and K. Henderson.
Rafael Fonseca, Martin M. Oken, and Philip R. Greipp, on behalf of the
Eastern Cooperative Oncology Group Myeloma
Group
Correspondence: Rafael Fonseca, Division of Hematology and
Internal Medicine, Mayo Building W10B, Rochester, MN 55905;
fonseca.rafael{at}mayo.edu.
Acknowledgments
R.F. is a Leukemia and Lymphoma Society
Translational Research Awardee. R.F. is also supported by the Mayo
Foundation and by the CI-5 Cancer Research Fund-Lilly Clinical
Investigator Award of the Damon Runyon-Walter Winchell Foundation.
Footnotes
Supported in part by Public Health Service grant R01 CA83724-01 from
the National Cancer Institute. The Mayo Foundation also supports this
study. Supported in part by research grant CA62242 (P.R.G. and B.V.N.).
Supported by the ECOG grant CA21115-25C from the National Cancer
Institute (P.R.G. and N.E.K.).
References
1.
Chesi M, Brents LA, Ely SA, et al.
Activated fibroblast growth factor receptor 3 is an oncogene that contributes to tumor progression in multiple myeloma.
Blood.
2001;97:729-736[Abstract/Free Full Text].
2.
Avet-Loiseau H, Facon T, Daviet A, et al.
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 Myelome.
Cancer Res.
1999;59:4546-4550[Abstract/Free Full Text].
3.
Fonseca R, Bailey R, Ahmann G, et al.
Translocations involving 14q32 are common in patients with the monoclonal gammopathy of undetermined significance. In: Proceedings from the International Myeloma Workshop, Stockholm, Sweden; 1999.
4.
Gabrea A, Bergsagel PL, Chesi M, Shou Y, Kuehl WM.
Insertion of excised IgH switch sequences causes overexpression of cyclin D1 in a myeloma tumor cell.
Molecular Cell.
1999;3:119-123[CrossRef][Medline]
[Order article via Infotrieve].
5.
Chesi M, Nardini E, Lim R, Smith K, Kuehl W, Bergsagel P.
The t(4;14) translocation in myeloma dysregulates both FGFR3 and a novel gene, MMSET, resulting in IgH/MMSET hybrid transcripts.
Blood.
1998;92:3025-3034[Abstract/Free Full Text].
6.
Chesi M, Nardini E, Brents LA, et al.
Frequent translocation t(4;14)(p16.3;q32.3) in multiple myeloma is associated with increased expression and activating mutations of fibroblast growth factor receptor 3.
Nat Genet.
1997;16:260-264[CrossRef][Medline]
[Order article via Infotrieve].
7.
Avet-Loiseau H, Li JY, Morineau N, et al.
Monosomy 13 is associated with the transition of monoclonal gammopathy of undetermined significance to multiple myeloma: Intergroupe Francophone du Myelome.
Blood.
1999;94:2583-2589[Abstract/Free Full Text].
8.
Fonseca R, Oken M, Harrington D, et al.
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[CrossRef][Medline]
[Order article via Infotrieve].
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
Related Article in Blood Online:
-
Activated fibroblast growth factor receptor 3 is an oncogene that contributes to tumor progression in multiple myeloma
- Marta Chesi, Leslie A. Brents, Sarah A. Ely, Carlos Bais, Davide F. Robbiani, Enrique A. Mesri, W. Michael Kuehl, and P. Leif Bergsagel
Blood 2001 97: 729-736.
[Abstract]
[Full Text]
[PDF]
This article has been cited by other articles:
|
|
|
|
 
G. W. Dewald, T. Therneau, D. Larson, Y. K. Lee, S. Fink, S. Smoley, S. Paternoster, A. Adeyinka, R. Ketterling, D. L. Van Dyke, et al.
Relationship of patient survival and chromosome anomalies detected in metaphase and/or interphase cells at diagnosis of myeloma
Blood,
November 15, 2005;
106(10):
3553 - 3558.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Chang, A. K. Stewart, X. Y. Qi, Z. H. Li, Q. L. Yi, and S. Trudel
Immunohistochemistry accurately predicts FGFR3 aberrant expression and t(4;14) in multiple myeloma
Blood,
July 1, 2005;
106(1):
353 - 355.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. C. Munshi, T. Hideshima, D. Carrasco, M. Shammas, D. Auclair, F. Davies, N. Mitsiades, C. Mitsiades, R. S. Kim, C. Li, et al.
Identification of genes modulated in multiple myeloma using genetically identical twin samples
Blood,
March 1, 2004;
103(5):
1799 - 1806.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Fonseca, B. Barlogie, R. Bataille, C. Bastard, P. L. Bergsagel, M. Chesi, F. E. Davies, J. Drach, P. R. Greipp, I. R. Kirsch, et al.
Genetics and Cytogenetics of Multiple Myeloma: A Workshop Report
Cancer Res.,
February 15, 2004;
64(4):
1546 - 1558.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Barlogie, J. Shaughnessy, G. Tricot, J. Jacobson, M. Zangari, E. Anaissie, R. Walker, and J. Crowley
Treatment of multiple myeloma
Blood,
January 1, 2004;
103(1):
20 - 32.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Fonseca, C. S. Debes-Marun, E. B. Picken, G. W. Dewald, S. C. Bryant, J. M. Winkler, E. Blood, M. M. Oken, R. Santana-Davila, N. Gonzalez-Paz, et al.
The recurrent IgH translocations are highly associated with nonhyperdiploid variant multiple myeloma
Blood,
October 1, 2003;
102(7):
2562 - 2567.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Soverini, M. Cavo, C. Cellini, C. Terragna, E. Zamagni, D. Ruggeri, N. Testoni, P. Tosi, A. de Vivo, M. Amabile, et al.
Cyclin D1 overexpression is a favorable prognostic variable for newly diagnosed multiple myeloma patients treated with high-dose chemotherapy and single or double autologous transplantation
Blood,
September 1, 2003;
102(5):
1588 - 1594.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Fonseca, E. Blood, M. Rue, D. Harrington, M. M. Oken, R. A. Kyle, G. W. Dewald, B. Van Ness, S. A. Van Wier, K. J. Henderson, et al.
Clinical and biologic implications of recurrent genomic aberrations in myeloma
Blood,
June 1, 2003;
101(11):
4569 - 4575.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Santra, F. Zhan, E. Tian, B. Barlogie, and J. Shaughnessy Jr
A subset of multiple myeloma harboring the t(4;14)(p16;q32) translocation lacks FGFR3 expression but maintains an IGH/MMSET fusion transcript
Blood,
March 15, 2003;
101(6):
2374 - 2376.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Moreau, T. Facon, X. Leleu, N. Morineau, P. Huyghe, J.-L. Harousseau, R. Bataille, and H. Avet-Loiseau
Recurrent 14q32 translocations determine the prognosis of multiple myeloma, especially in patients receiving intensive chemotherapy
Blood,
August 13, 2002;
100(5):
1579 - 1583.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Fonseca, R. J. Bailey, G. J. Ahmann, S. V. Rajkumar, J. D. Hoyer, J. A. Lust, R. A. Kyle, M. A. Gertz, P. R. Greipp, and G. W. Dewald
Genomic abnormalities in monoclonal gammopathy of undetermined significance
Blood,
July 30, 2002;
100(4):
1417 - 1424.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Avet-Loiseau, T. Facon, B. Grosbois, F. Magrangeas, M.-J. Rapp, J.-L. Harousseau, S. Minvielle, and R. Bataille
Oncogenesis of multiple myeloma: 14q32 and 13q chromosomal abnormalities are not randomly distributed, but correlate with natural history, immunological features, and clinical presentation
Blood,
March 15, 2002;
99(6):
2185 - 2191.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Fonseca, D. Harrington, M. M. Oken, G. W. Dewald, R. J. Bailey, S. A. Van Wier, K. J. Henderson, E. A. Blood, S. V. Rajkumar, N. E. Kay, et al.
Biological and Prognostic Significance of Interphase Fluorescence in Situ Hybridization Detection of Chromosome 13 Abnormalities ({Delta}13) in Multiple Myeloma: An Eastern Cooperative Oncology Group Study
Cancer Res.,
February 1, 2002;
62(3):
715 - 720.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
