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Blood, Vol. 94 No. 8 (October 15), 1999:
pp. 2583-2589
Monosomy 13 Is Associated With the Transition of Monoclonal
Gammopathy of Undetermined Significance to Multiple Myeloma
By
Hervé Avet-Loiseau,
Jian-Yong Li,
Nadine Morineau,
Thierry Facon,
Christophe Brigaudeau,
Jean-Luc Harousseau,
Bernard Grosbois, and
Régis Bataille on behalf of the Intergroupe Francophone du
Myélome
From the Laboratory of Hematology, the Clinical Hematology
Department, Centre Hospitalier Universitaire, Nantes, France; the
Service des Maladies du Sang, Centre Hospitalier Universitaire, Lille,
France; the Laboratory of Hematology, Centre Hospitalier Universitaire,
Limoges, France; and the Service of Internal Medicine, Centre
Hospitalier Universitaire, Rennes, France.
 |
ABSTRACT |
Chromosomal abnormalities are present in most (if not all) patients
with multiple myeloma (MM) and primary plasma cell leukemia (PCL).
Furthermore, recent data have shown that numerical chromosomal changes
are present in most individuals with monoclonal gammopathy of
undetermined significance (MGUS). Epidemiological studies have shown
that up to one third of MM may emerge from pre-existing MGUS. To
clarify further possible stepwise chromosomal aberrations on a pathway
between MGUS and MM, we have analyzed 158 patients with either MM or
primary PCL and 19 individuals with MGUS using fluorescence in situ
hybridization (FISH). Our FISH analyses were designed to detect
illegitimate IGH rearrangements at 14q32 or monosomy 13. Whereas translocations involving the 14q32 region were observed with a
similar incidence (60%) in both conditions, a significant difference
was found in the incidence of monosomy 13 in MGUS versus MM or primary
PCL. It was present in 40% of MM/PCL patients, but in only 4 of 19 MGUS individuals. Moreover, whereas monosomy 13 was found in the
majority of plasma cells in MM, it was observed only in cell
subpopulations in MGUS. It is noteworthy that, in a group of 20 patients with MM and a previous MGUS history, incidence of monosomy 13 was 70% versus 31% in MM patients without a known history of MGUS
(P = .002). Thus, this study highlights monosomy 13 as
correlated with the transformation of MGUS to overt MM and may define 2 groups of MM with possible different natural history and outcome, ie,
post-MGUS MM with a very high incidence of monosomy 13 and de novo MM
in which other genetic events might be involved. Serial analyses of
individuals with MGUS will be needed to validate this model.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
MULTIPLE MYELOMA (MM), a disorder in
which malignant plasma cells (PC) accumulate in the bone marrow, is
responsible for approximately 1% of all cancer-related mortality in
Western countries. Specific chromosomal abnormalities have been
implicated in the oncogenesis of several hematologic malignancies.
Translocations t(9;22) in chronic myeloid leukemia, t(15;17) in acute
promyelocytic leukemia, and t(11;14) in mantle cell lymphoma are
characteristic examples. In MM, the situation is far less clear. First
of all, cytogenetic analyses are hampered by the low proliferative rate of PC. Consequently, 50% to 70% of patients display a normal
karyotype, because only normal metaphase bone marrow cells are in cycle
and able to be analyzed.1-6 In fact, recent studies based
on interphase fluorescence in situ hybridization (FISH) have shown that
virtually 100% of MM patients have chromosomal abnormalities in their
plasma cells.7-9 The second problem is the absence of any
common specific abnormality. Many recurrent chromosomal changes have
been described, including gains of odd chromosomes, rearrangements of
the 14q32 region, or monosomy 13.1-6,10,11 However, none of
these abnormalities is myeloma-specific or found in a large majority of
MM patients.
Significant advances have been made with the recent demonstration that
most human myeloma cell lines12 and 60% to 75% of MM
patients13,14 have an illegitimate rearrangement involving the IGH gene at 14q32. We have recently shown that 60% of MM
patients display such a rearrangement, especially through reciprocal
translocations, and that the main partner chromosomal regions were
11q13 and 4p16.14,15 Moreover, we have shown that the
incidence of these abnormalities was independent of the clinical stage,
supporting the hypothesis that they occur early in the natural history
of the disease.14 Finally, we have shown that these
rearrangements were found in all of the tumor cells in a given patient,
strongly implicating them as an early key event preceding clonal expansion.
MM has been clinically and pathophysiologically related to another
condition termed monoclonal gammopathy of undetermined significance
(MGUS). Analysis of bone marrow in MGUS is usually normal, but in a
significant percentage of cases, an increased percentage of PC is
found. Individuals with MGUS show a significant risk of progression to
MM, with an annual actuarial risk of malignant transformation of
0.8%.16 A recent report from the Mayo Clinic has shown
that 33% of newly diagnosed MM patients had a previous MGUS
history.17 Analyses of chromosomal abnormalities in
individuals with MGUS have shown that numerical changes were present in
their PC.18-20 All of these data support the hypothesis of
a possible link between MGUS and MM, with MGUS being a premalignant
condition that could evolve to overt MM in some individuals with
accumulation of further genetic events. A pending question remains as
to whether all MM emerge from a pre-existing MGUS (ie, post-MGUS MM) or
not (ie, de novo MM).
To gain insight into these questions, we have analyzed by FISH 19 individuals with MGUS, in comparison with 144 patients with MM and 15 with primary plasma cell leukemia (PCL). We searched for a specific
abnormality (or abnormalities) that correlated with malignant
transformation from MGUS into overt MM. In other words, do detectable
genetic differences exist between these 2 conditions? To answer these
questions, we looked for 3 of the 4 most common specific translocations
involving IGH, ie, t(4;14),14,15,21,22 t(8;14),1-6 t(11;14),1-6,14,15 and the most
frequent chromosomal loss, ie, monosomy 13, using interphase FISH.
| |
PATIENTS, MATERIALS, AND METHODS |
Patients.
We analyzed 19 individuals with MGUS, according to standard criteria:
less than 30 g/L of serum M-component, less than 10% PC in bone
marrow, absence of lytic bone lesions on radiography, and no anemia or
hypercalcemia. Two patients with AL
amyloidosis and renal insufficiency, but lacking any symptom of overt
MM, were included in this MGUS population. Serum monoclonal Ig levels were stable for at least 12 months. Follow-up ranged from 12 to 101 months. Age at diagnosis ranged from 48 to 86 years (median, 68 years).
The M-component was IgG in 8 patients, IgG in 5 patients, and
IgA in 6 patients. Pertinent features of these individuals are
outlined in Table 1.
These 19 individuals with MGUS were compared with a series of 158 patients with plasma cell disorders, including 13 indolent MM,23 17 newly diagnosed stage I MM,24 27 stage
II, 58 stage III patients, 15 primary PCL patients, and 28 patients at
relapse. Except for these last patients, who were studied at first
relapse (after achievement of at least a partial response), all of the other patients were studied before any treatment. These patients have
been previously described in detail.14 Moreover, to better evaluate the tumor mass, we recorded the serum  2-microglobulin for
most and correlated it with chromosomal findings.
PC purification.
Bone marrow aspirates were collected into heparin as an anticoagulant.
Mononuclear cells were separated by density gradient centrifugation
(Ficoll-Hypaque). For the first 72 patients, malignant plasma cells
were identified using control probes specific for previously detected
numerical abnormalities.14 Because CD138 is expressed only
on PC within the bone marrow, we then used the anti-CD138 B-B4
monoclonal antibody to obtain highly purified plasma cells as
previously described25 in the subsequent 86 patients.
Mononuclear cells were washed in phosphate-buffered saline (PBS) and
then incubated with anti-CD138 antibodies for 15 minutes at 4°C.
After 2 washes in PBS, magnetic beads coated with IgG1 (Miltenyi
Biotec, Paris, France) were added, and PC were purified on columns
using a magnet, according to the manufacturer's instructions. After a
final wash in PBS, the percentage of PC was determined on
cytocentrifuge slides (median, 93%; range, 78% to 99%). Purified
cells were then incubated in hypotonic KCl and fixed in methanol/acetic
acid (3/1). In MGUS, PC were also purified using the anti-CD138-coated
magnetic beads. Because nonclonal PC may persist in the bone marrow of
MGUS patients (even if usually at a low percentage; data not shown), we
performed interphase FISH with centromeric probes specific for the main
additional chromosomes, ie, 3, 7, 9, 11, 15, 17, 18, and X, to evaluate
the number of clonal PC (see below).
FISH.
FISH was performed as previously reported.14,15 Briefly,
50 ng of each unique sequence probe was ethanol-precipitated
with 1 µg of Cot-1 DNA. After resuspension in Hybrisol VII (Oncor, Gaithersburg, MD), probes were denatured at 75°C for 10 minutes and
placed at 37°C for 15 to 30 minutes for preannealing. After overnight
hybridization, slides were washed and nuclei were counterstained with
4',6-diamidino-2-phenylindole in antifade. Repetitive
centromeric probes were used as previously reported.14
Probes.
The IGH locus was analyzed using 3 probes, as previously
described14: a BAC probe (158A2) previously
described,26 the Y6 YAC, and the Ig10 cosmid probes, kindly
provided by Dr F. Matsuda (Kyoto University, Kyoto, Japan) and Dr T.H.
Rabbits (Medical Research Council, Cambridge, UK),
respectively. The FGFR3 locus was analyzed using
the PAC probe described by Chesi et al.21 The probes were
validated in the OPM2 and NCI-H929 human myeloma cell lines (HMCL), as
previously reported.15 Translocation t(4;14) was shown by a
fusion signal on the der(14) (Fig 1A). The
MYC locus was analyzed using 2 YAC probes (I2 and P72;
generously provided by Dr M.L. Veronese, Jefferson Cancer Institute,
Philadelphia, PA). These probes have been validated in 15 cases of Burkitt's lymphoma with t(8;14). The translocation was shown
as 1 or 2 fusion signals on the der(14) and sometimes on the der(8)
(Fig 1B). These different probes were labeled using standard nick
translation, with biotin-dUTP (Boehringer Mannheim, Mannheim, Germany),
fluorescein isothiocyanate (FITC)-dUTP, Coumarin-dUTP (NEN, Postfach,
Germany), Cyanin5-dUTP (Amersham, Les Ulis, France), and
SpectrumOrange-dUTP (Vysis, Downers Grove, IL). The
CCND1 probe was provided by Vysis and was validated in mantle
cell lymphoma cases and in the U266, XG1, and XG5 HMCL (Fig 1C). We
first looked for illegitimate IGH rearrangements using the Y6
and Ig10 probes. We then looked for specific 14q32 translocation
partners, even in patients without illegitimate IGH
rearrangements, to assess the specificity of our FISH methodology in
detecting 14q32 translocations. In this second step, the 14q32 region
was analyzed using a combination of the Ig10 and 158A2 probes (thus
covering the whole constant domain), labeled in green, and the partner
regions were analyzed using the specific probes labeled in orange.
Finally, chromosome 13 was analyzed using 2 probes: a D13S319-probe
mapping at 13q14 provided by Vysis and a YAC probe mapping at 13q31.
FISH results were compared with karyotype when available (clonal
abnormalities in 38 of 77 patients analyzed).
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| Fig 1.
(A) Photograph of a malignant PC with t(4;14) and
deletion 13q. The 4p16 (FGFR3) probe is labeled in red, whereas
the 14q32 probes (Ig10 and 158A2) are labeled in green and the 13q32
probe in white/grey. The t(4;14) is represented by the fusion signal
and the normal chromosomes 4 and 14 by the red and green signals,
respectively. Only 1 white signal is observed, reflecting deletion 13q.
(B) A plasma cell of a patient with t(8;14)(q24;q32). The translocation
is identified by the fusion of 1 green (14q32 probe) and 1 red (8q24)
signal. The separated green and red signals correspond to the normal
chromosomes 14 and 8, respectively. Finally, this patient did not
display chromosome 13 monosomy, because 2 white signals (13q32 probe)
were observed. (C) Translocation t(11;14)(q13;q32), not associated with
monosomy 13, in a patient with multiple myeloma. The fusion of 1 green
(14q32 probe) and 1 red (11q13 probe) signal corresponds to the
derivative chromosome 14, whereas the separated green and red signals
represent normal chromosomes 14 and 11, respectively. Two white signals
(13q32 probe) are observed.
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Statistical analyses.
For statistical analyses, we used nonparametric tests, mainly the
 2 method.
| |
RESULTS |
IGH analysis and validation of probes.
Illegitimate IGH rearrangements were analyzed with the Y6 and
Ig10 probes. Absence of IGH abnormality (ie, 2 normal
chromosome 14) was assessed when 2 yellow signals were found
(colocalization of Y6 and Ig10 probes, configuration YY). Monosomy 14 or loss of the IGH locus were defined by the presence of only 1 fusion signal (configuration Y). All other configurations corresponded to an illegitimate recombination. The most frequent abnormal figure was
1 yellow signal (ie, the normal chromosome 14), 1 green signal (ie, the
derivative chromosome 14 labeled with the Ig10 probe), and 1 orange
signal (ie, the derivative partner chromosome) (configuration YGO). In
some instances, we found 1 yellow signal (normal chromosome 14) and 1 green signal (derivative chromosome 14) (configuration YG). This
disposition was interpreted as a deletion of the IGH 5' part or
as a loss of the derivative partner chromosome. Probes were validated
on bone marrow cells obtained from healthy donors. Two thousand cells
were scored with the Y6 and Ig10 probes. A normal configuration (2 yellow signals) was found in 96% of nuclei. Cut-off for the assessment
of an illegitimate IGH rearrangement was 8.7% (mean + 3 SD).
Chromosome 13-specific probes were validated in the same way.
Dual-color hybridizations were performed with the 2 probes. Based on
analysis of 4,000 peripheral blood mononuclear cells from 10 healthy
individuals, cut-off for deletion (mean + 3 SD) was 5.3% for the
13q14 probe and 8.6% for the 13q31 probe.
14q32 abnormalities are observed in 59% of patients with malignant
plasma cell disorders, but correlate neither with disease stage nor
with progression.
An illegitimate IGH rearrangement was found in 93 of 158 (59%)
patients with MM or primary PCL (Table 2).
Analysis of 14q32 abnormalities according to disease stage and status
did not show any significant difference. An abnormal FISH probe
disposition was found in 10 of 13 (77%), 10 of 17 (59%), 17 of 27 (63%), 34 of 58 (59%), 11 of 14 (79%), and 11 of 28 (39%) patients
with indolent, stage I, stage II, stage III, primary PCL, and in first relapse, respectively. We then analyzed the 4p16 (FGFR3), 8q24 (MYC), and 11q13 (CCND1) regions. We found a
t(11;14)(q13;q32) (ie, IGH-CCND1 fusion) in 26 patients, a
t(4;14)(p16;q32) (ie, IGH-FGFR3 fusion) in 19 patients, and a
t(8;14)(q24;q32) (ie, IGH-MYC fusion) in 3 patients. As
expected, all of the cases with fusion were found in patients with an
illegitimate IGH rearrangement. Comparison of FISH results with
karyotype for the 38 patients with clonal abnormalities showed
discrepancies in 11 patients. In 10 cases, illegitimate IGH
rearrangements were observed by FISH, whereas cytogenetics did not
detect any 14q32 abnormality. Of note, 5 of these 10 patients displayed
a t(4;14)(p16;q32), which is not detectable by cytogenetics. In 1 patient, cytogenetics detected an add(14q32), whereas no illegitimate
rearrangement was found by FISH. An extensive analysis of the
IGH gene using numerous FISH probes failed to detect
illegitimate recombinations. Thus, this patient had a 14q32 abnormality
that did not involve the IGH gene.
No significant correlation between specific rearrangement and disease
stage was found. We also correlated 14q32 abnormalities with the
2-microglobulin level. In the group of patients with 2-microglobulin less than 3 mg/L (this cut-off value has been determined as highly significant for prognosis in the IFM94 protocol; unpublished data), 24 of 36 (67%) displayed an illegitimate
IGH rearrangement, as opposed to 34 of 59 (58%) in the group
of patients with 2-microglobulin greater than 3 mg/L.
These results confirmed the absence of any statistically significant
correlation between 14q32 abnormalities and tumor mass.
Monosomy 13 is observed in 39% of patients with malignant plasma
cell disorders, but correlates neither with disease stage nor with
progression.
Deletion of the 13q14 region was found in 60 of 158 (38%) patients
with either MM or primary PCL. Most of these deletions probably
correspond to chromosome 13 monosomies (or at least large deletions),
because the 13q31 region was concomitantly lost in 57 of 60 patients.
Comparison of FISH and cytogenetic results was in complete agreement:
the 16 patients with only one 13q14 signal by FISH displayed monosomy
13 on karyotyping. These chromosome 13 abnormalities were found in 64%
to 96% of plasma cells (mean, 83%; SD, 9.94%) and, thus, are
considered as secondary events. The incidences of 13q14 deletions were
23% (3/13), 35% (6/17), 44% (12/27), 38% (22/58), 53% (8/15), and
32% (9/28) in patients with indolent, stage I, stage II, stage III,
primary PCL, and relapse MM, respectively (no significant difference).
Correlation with 2-microglobulin gave similar results: in the
low-level group, 14 of 36 patients (39%) displayed a monosomy 13, whereas in the high-level group, 24 of 59 (41%) displayed such a
monosomy. Finally, we analyzed the incidence of monosomy 13 within each
14q32 subgroup, ie, patients without IGH abnormality, patients
with t(4;14), patients with t(11;14), and patients with other
IGH abnormalities. Clearly, monosomy 13 was more frequent in
patients with t(4;14) than in patients with either t(11;14)
(P < .002) or lacking 14q32 abnormalities (P < .001).
As opposed to 14q32 translocations, monosomy 13 is less frequently
observed in individuals with MGUS.
Besides these 158 patients with either MM or primary PCL, we analyzed
19 individuals with MGUS. Their main bioclinical features are described
in Table 1. Illegitimate IGH rearrangements were observed in 11 of 19 cases (58%). This incidence is similar to that found in patients
with MM and PCL. Partner chromosome analysis identified
t(11;14)(q13;q32) in 3 cases and t(4;14)(p16;q32) in 1 case. No other
specific rearrangement was found. Monosomy of chromosome 13 was
observed in 4 of 19 individuals (21%), in 80%, 40%, 33%, and 18%
of PC, respectively (patients no. 6, 8, 13, and 16). To know if
monosomy 13 was present only in clonal PC in these 3 latter patients
with low percentage of 13q PC, we performed FISH experiments
combining the D13S319 probe with centromeric probes specific for gained
chromosomes or with the 14q32 probes when illegitimate IGH
rearrangements were present in these patients (Fig 2A and
B). In these 3 patients, we observed clonal
chromosomal changes in 86%, 73%, and 82% of PC, thus confirming that
monosomy 13 was only present in clonal PC subpopulations. Because the
absence of illegitimate IGH rearrangement could be related to a
low percentage of clonal PC, we performed in the 5 patients lacking
both 14q32 and 13q14 abnormalities FISH analysis with the centromeric
probes. Trisomies were detected in 3 of them (trisomies 3, 9, 11, and 15 in 2 cases, and trisomies 9 and 15 in 1 case), respectively, in
83%, 57%, and 62% of PC. Thus, PC of these 3 individuals did not
display illegitimate IGH rearrangements.
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| Fig 2.
(A) Analysis of a purified plasma cell of MGUS individual
no. 16, using the Y6, IG10, and 13q32 probes. The yellow signal
corresponds to the fusion of 1 green (IG10 probe) and 1 red (Y6 probe)
on a normal chromosome 14. The second chromosome 14 is rearranged,
because the Y6 and the IG10 probes are separated. This clonal plasma
cell is disomic for chromosome 13 (2 white signals). (B) Another plasma
cell of the same patient. In contrast to the cell shown in (A), this
clonal plasma cell (with an illegitimate IGH rearrangement)
displays deletion 13q (only 1 white signal).
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Monosomy 13, but not 14q32 translocations, discriminates post-MGUS MM
from de novo MM.
Recently, Kyle et al17 have shown that 33% of MM in their
series occurred in patients with a previous MGUS history. In our current series, an MGUS history was documented in 20 patients with
either MM or primary PCL (20/130 patients at diagnosis, ie, 15% of
patients). In this subset of patients, 14q32 abnormalities were
observed in 12 of 20 (60%) patients (1 case with IGH-CCND1 fusion and 1 case with IGH-FGFR3 fusion), thus at a similar
incidence to that found in de novo MM and primary PCL (70/110 [64%];
P = .97). In contrast, incidence of deletion 13q14 was
significantly different in each group: 14 of 20 (70%) in post-MGUS MM
versus 29 of 95 (31%) in de novo MM at diagnosis (P = .002).
Monosomy 13 is an important event in the transition from MGUS to MM.
When MGUS and post-MGUS MM were analyzed in parallel, monosomy 13 was
found in 4 of 19 of MGUS but in 14 of 20 post-MGUS MM (P = .006), underlining that monosomy 13 appears to represent an important event in the transition from MGUS to MM. In the current study, MGUS and post-MGUS MM are 2 different populations of patients. Thus, serial evaluation of individuals with MGUS will be necessary to
validate this point. However, the fact that 3 patients with MGUS had
monosomy 13 in subsets of their plasma cells (18%, 33%, and 40%,
respectively) emphasizes the possibility of such malignant transformation at the cellular level through monosomy 13.
| |
DISCUSSION |
Chromosomal abnormalities are present in virtually 100% of MM
patients.7-9 However, their characterization is often
hampered by the low proliferative rate of myeloma cells. The situation is even more prominent in PC of individuals with MGUS. Cytogenetic abnormalities are very rarely detected in MGUS. Only 1 report described
cytogenetic abnormalities in 11 of 44 individuals with MGUS.6 However, these abnormal karyotypes were strikingly
different from those found in MM (high percentage of cytogenetically
abnormal cells, but no numerical abnormality, with usually 1 single
structural rearrangement). Nevertheless, a few reports based on
interphase FISH clearly demonstrated that at least numerical changes
are present in the majority of individuals with this indolent
condition.18,19 Recently, Zandecki et al20
showed that, in contrast to myeloma cells, which are usually really
monoclonal, several cytogenetic subclones may coexist within these
cases of MGUS. This finding might be interpreted as an ongoing
tumorigenic process leading to overt MM with time. This hypothesis is
corroborated by the finding that some individuals with MGUS still
acquire mutations in their Ig genes, whereas patients with MM exhibit
heavily mutated PC.27 This finding reflects the fact that
MGUS PC are still under the exposure of the mutator.
To elucidate the oncogenetic events in MM, and especially those
involved in the MGUS/MM transition, we analyzed by FISH chromosome 13 and 14q32 rearrangements in 19 individuals with MGUS and 158 patients
with either MM or primary PCL. We found illegitimate IGH
recombinations in 11 of 19 individuals with MGUS (58%) and in 93 of
158 patients with plasma cell malignancies (59%). This similar
incidence favors the hypothesis that these illegitimate rearrangements
occur very early in the tumorigenic process leading to MM and may be
not sufficient for complete malignant transformation. Moreover, in
contrast to numerical changes, we demonstrated that PC of individuals
with MGUS are very homogeneous regarding these structural
rearrangements. These numerical chromosomal abnormalities are more
likely secondary events. However, because they are not found in all the
cases of MGUS or MM, illegitimate IGH recombinations are
probably not the only event implicated in tumorigenesis. We were able
to characterize the partner chromosome in 4 of 19 MGUS cases. The 11q13
region was involved in 3 cases, whereas the 4p16 region was involved in
1 case. These 2 chromosomal regions are also the most frequently
involved in MM and primary PCL in our series.
Another chromosomal abnormality that has been associated with poor
prognosis in MM is deletion or monosomy 13.9,11,28 Analysis
of 130 patients with MM or primary PCL at diagnosis showed that this
abnormality is found in 39% of cases. Even though this abnormality is
probably a secondary event, because it is not found in all myeloma
cells, it is present in the majority of PC. This finding supports the
hypothesis that this chromosomal change occurs as a secondary event,
but that it then confers a selective growth or survival advantage.
However, this secondary event does not appear to occur during disease
progression, because the analysis of patients at relapse did not show a
higher incidence (9/28 [32%]). It is noteworthy that
deletion/monosomy 13 appears to be associated with some particular
14q32 abnormalities. It is significantly more frequently found in
association with illegitimate IGH rearrangements and especially
with t(4;14). In contrast, it is less frequently found in patients with
t(11;14) or lacking illegitimate IGH rearrangements. The
reasons for these associations are currently unknown.
It is of major interest that the incidence of deletion/monosomy 13 was
significantly lower in MGUS than in MM and primary PCL, supporting the
hypothesis that loss of chromosome 13 may play a role in the MGUS/MM
transition. This hypothesis is strongly reinforced by the finding that
monosomy 13 incidence is much higher in post-MGUS MM than in so-called
de novo MM. A careful literature analysis of large cytogenetics series
enabled us to find 1 recent report in which such data were available.
Smadja et al29 described 6 patients with post-MGUS MM in a
cytogenetic series of 81 patients. Whereas chromosome 13 deletions were
present in 33 of 75 (44%) patients without any known MGUS history,
monosomy 13 was found in 5 of 6 (83%) cases of post-MGUS MM.
In this model, the loss of chromosome 13 sequences would precipitate
long-lived plasma cells (possibly previously modified by other genetic
events, such as 14q32 abnormalities) into myeloma cells. In this model,
our 3 MGUS individuals with monosomy 13 in only PC subsets may
correspond to transitional conditions. In these cases, we could
hypothesize that the clone with monosomy 13 will progress and that
these 3 patients will rapidly evolve to overt MM. Our model is even
more supported by the fact that 4 of the 20 patients with post-MGUS MM
had an indolent disease and that monosomy 13 was found in only 1 of
these 4 patients. Thus, monosomy 13 would be involved in the
transformation of MGUS into overt aggressive MM (Fig
3).
Because deletion/monosomy 13 is found more frequently in MM patients
with MGUS history, we can hypothesize the existence of 2 kinds of MM.
One group would emerge as a malignant transformation of MGUS, and loss
of chromosome 13 could participate in this transformation. A second
group would be the de novo MM, in which chromosome 13 would have less
importance in oncogenesis. In this scheme, the worse prognosis found in
patients with loss of chromosome 13 would be the consequence of a
different disease, more chemoresistant, as shown in another model, ie,
acute myeloid leukemia with previous myelodysplasia and abnormalities
of chromosomes 5 and 7. Because MGUS is an asymptomatic condition, some
MM may occur in individuals with an undiagnosed MGUS. In the experience
of Kyle et al,17 at least 33% of MM would emerge from
MGUS. This incidence is close to that of monosomy 13 in MM
(35% to 40%). An attractive hypothesis would be to associate these 2 groups of MM (post-MGUS MM and those with monosomy 13) in a single
disease. In this model, the poor prognosis associated with monosomy
139,11,28 would be the consequence of the secondary
character of these MM, as recently proposed in acute myeloid leukemia
with deletion of chromosomes 5 and 7. To answer this important
question, long-term follow-up and repetitive appropriate biological
evaluations of large cohorts of individuals with MGUS will be needed.
Especially serial evaluation of the same patients recognized at MGUS,
followed without treatment while asymptomatic and then at the emergence
of overt myeloma, should help to clarify the impact of specific
chromosome abnormalities. From this point of view, careful follow-up of
individuals with MGUS and monosomy 13 in PC subpopulations should be of
major interest. The answer might also be given by the Mayo Clinic group
by analyzing their cohort of post-MGUS versus de novo MM.
In conclusion, we demonstrated that illegitimate IGH
rearrangements are present in patients with MGUS, with exactly the same incidence as in MM and primary PCL patients. In contrast, monosomy 13 seems to be rather infrequent in MGUS, whereas it is found in 40% of
MM and in 70% of post-MGUS MM and thus is a good candidate event for
the malignant transformation of myeloma cells. However, because most
chromosome 13 abnormalities are monosomies or large deletions, many
genes may be implicated in this oncogenic process.
| |
FOOTNOTES |
Submitted October 19, 1998; accepted June 6, 1999.
Supported in part by the Fondation contre la Leucémie and the
Comité Départemental de Loire-Atlantique de la Ligue contre le Cancer. J.-Y.L. is a grant recipient of the Conseil Régional des Pays de Loire.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Hervé Avet-Loiseau, MD, PhD, or
Régis Bataille, MD, PhD, Laboratoire d'Hématologie,
Institut de Biologie, 9, quai Moncousu, 44093 Nantes Cedex 1, France;
e-mail: havetloiseau{at}chu-nantes.fr.
| |
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ABSTRACT
INTRODUCTION
