Molecular cytogenetic aberrations in patients with multiple myeloma studied by interphase fluorescence in situ hybridization
Background: Multiple myeloma (MM) is an incurable hematological disorder characterized by the accumulation of malignant plasma cells within the bone marrow (BM). The clinical heterogeneity of MM is dictated by the cytogenetic aberrations present in the clonal plasma cells (PCs). Cytogenetic studies...
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Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України
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| Zitieren: | Molecular cytogenetic aberrations in patients with multiple myeloma studied by interphase fluorescence in situ hybridization / L.J. Chen, J.Y. Li, W. Xu, H.R. Qiu, Y. Zhu, Y.P. Zhang, L.M. Duan, S.X. Qian, H. Lu // Experimental Oncology. — 2007. — Т. 29, № 2. — С. 116–120. — Бібліогр.: 28 назв. — англ. |
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Digital Library of Periodicals of National Academy of Sciences of Ukraine| _version_ | 1860080203884134400 |
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| author | Chen, L.J. Li, J.Y. Xu, W. Qiu, H.R. Zhu, Y. Zhang, Y.P. Duan, L.M. Qian, S.X. Lu, H. |
| author_facet | Chen, L.J. Li, J.Y. Xu, W. Qiu, H.R. Zhu, Y. Zhang, Y.P. Duan, L.M. Qian, S.X. Lu, H. |
| citation_txt | Molecular cytogenetic aberrations in patients with multiple myeloma studied by interphase fluorescence in situ hybridization / L.J. Chen, J.Y. Li, W. Xu, H.R. Qiu, Y. Zhu, Y.P. Zhang, L.M. Duan, S.X. Qian, H. Lu // Experimental Oncology. — 2007. — Т. 29, № 2. — С. 116–120. — Бібліогр.: 28 назв. — англ. |
| collection | DSpace DC |
| container_title | Experimental Oncology |
| description | Background: Multiple myeloma (MM) is an incurable hematological disorder characterized by the accumulation of malignant plasma cells within the bone marrow (BM). The clinical heterogeneity of MM is dictated by the cytogenetic aberrations present in the clonal plasma cells (PCs). Cytogenetic studies in MM are hampered by the hypoproliferative nature of plasma cells in MM. Therefore, fluorescence in situ hybridization (FISH) analysis combined with magnetic-activated cell sorting (MACS) is an attractive alternative for evaluation of numerical and structural chromosomal changes in MM. Methods: Interphase FISH studies with three different specific probes for the regions containing 13q14.3 (D13S319), 14q32 (IGHC/IGHV) and 1q12(CEP1 ) were performed in 48 MM patients. Interphase FISH studies with LSI IGH/CCND1, LSI IGH/FGFR3, and LSI IGH/MAF probes were used to detect t(11;14)(q13;q32), t(4;14)(p16;q32), and t(14;16)(q32;q23) in patients with 14q32 rearrangement. Results: Molecular cytogenetic aberrations were found in 40 (83.3%) of the 48 MM patients. 13 patients (27.1%) simultaneously had 13q deletion/monosomy 13 [del(13q14)], illegitimate IGH rearrangement and chromosome 1 abnormality. Del(13q14) was detected in 21 cases (43.7%), and illegitimate IGH rearrangements in 29 (60.4%) including 6 with t(11;14) and 5 with t(4;14). None of 9 patients with illegitimate IGH rearrangements and without t(11;14) or t(4;14) we detected had t(14;16) (q32;q23). 24 of the 48 MM patients (50%) had chromosome 1 abnormalities. Among 21 patients with del(13q14), 15 patients had Amp1q12;16 had IgH rearrangements. Whereas, among 27 cases without del(13q14), 8 had Amp1q12; 13 had IgH rearrangements. There was a strong association between del(13q14) and Amp1q12(c2 = 8.26, р < 0.01), and between del(13q14) and IgH rearrangement(c2 = 3.88, p < 0.05). Conclusion: 13q deletion/monosomy 13, IGH rearrangement and chromosome 1 abnormality are frequent in MM. They are not randomly distributed, but strongly interconnected. Interphase FISH technique combined with MACS using CD138-specific antibody is a highly sensitive technique at detecting molecular cytogenetic aberrations in MM.
Обоснование: множественная миелома (MM) — неизлечимое гематологическое заболевание, характеризирующееся
накоплением злокачественных плазматических клеток в костном мозге (КM). Клиническая гетерогенность MM определяется
цитогенетическими аберрациями, присутствующими в клоне плазматических клеток (ПК). Цитогенетические исследования
MM осложнены гипопролиферативными особенностями ПК. В связи с этим флуоресцентная гибридизация in situ (FISH)
в комбинации с сортировкой клеток, активированных магнитными полями (MACS) представляется достойной альтернативой
методам оценки точечных и структурных изменений хромосом при MM. Методы: интерфазные исследования методом
FISH с использованием трех различных специфических зондов для участков, содержащих 13q14.3 (D13S319), 14q32
(IGHC/IGHV) и 1q12(CEP1), проводили у 48 больных с MM. Интерфазные исследования методом FISH с использованием
зондов LSI IGH/CCND1, LSI IGH/FGFR3 и LSI IGH/MAF применяли для детекции t(11;14)(q13;q32), t(4;14)(p16;q32), и
t(14;16)(q32;q23) у пациентов с перестройкой 14q32. Результаты: молекулярные цитогенетические аберрации выявляли у
40 (83,3%) из 48 больных с MM. У 13 пациентов (27,1%) одновременно определены 13q делеция/моносомия 13 [del(13q14)],
аномальная перестройка IGH и аномалия хромосомы 1. Del(13q14) детектировали в 21 случае (43,7%), а аномальные
перестройки IGH — в 29 (60,4%), в том числе у 6 пациентов с t(11;14) и 5 с t(4;14). Ни у одного из 9 больных с аномальными
перестройками IGH и без t(11;14) или t(4;14) не выявляли транслокацию t(14;16) (q32;q23). У 24 из 48 пациентов с MM
(50%) определяли аномалии хромосомы 1. В группе из 21 больных с del(13q14) в 15 случаях имелись перестройки IgH
Amp1q12;16. В то же время из 27 случаев без del(13q14) у 8 содержались Amp1q12; в 13 случаях отмечали перестройки
IgH. Выявлена взаимосвязь между del(13q14) и Amp1q12(χ2
= 8,26, p < 0,01) и между del(13q14) и перестройками IgH
(χ2 = 3,88, p < 0,05). Выводы: 13q делецию/моносомию 13, перестройку IGH и аномалию хромосомы 1 часто отмечают
при MM, причем их распределение не случайно и тесно взаимосвязано. Интерфазный анализ FISH в комбинации с
MACS с использованием CD138-специфичных антител является высокочувствительным методом детекции молекулярных
цитогенетических аберраций при MM.
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| first_indexed | 2025-12-07T17:15:54Z |
| format | Article |
| fulltext |
116 Experimental Oncology 29, 116–120, 2007 (June)
Multiple myeloma (MM) is a terminally differentia
ted clonal Bcell neoplasm characterized by the ac
cumulation of malignant plasma cells (PCs) within the
bone marrow (BM). Its prognosis is highly variable,
with survival ranging from a few days to more than
10 years [1, 2]. A median survival of about 3 years was
obtained with conventional chemotherapy. Despite
improvements in the clinical management of patients
in the past decade, especially with the use of highdose
therapy followed by autologous stem cell transplanta
tion [3] and with the use of new drugs such as thalido
mide, lenalidomide and proteasome inhibitors [4–6],
MM remains incurable. Therefore, it appears essential,
at diagnosis, to recognize clinical or biological parame
ters predicting the outcome and identifying patients
for whom an aggressive therapy would be indicated.
Molecular cytogenetic studies have revealed that,
to a great extent, the clinical heterogeneity of MM is
dictated by the cytogenetic aberrations present in the
clonal plasma cells. Karyotypic deletion of chromo
some 13, hypodiploidy, and molecular cytogenetics are
specific independent prognostic factors for accurate
risk stratification in MM [7].
Although there are many reports that cytogenetic
changes are associated with prognosis, cytogenetic
studies in MM are hampered by the hypoproliferative
nature of clonal PCs in MM. Abnormal karyotypes
have been reported only in 30–45% of de novo cases,
and 35–60% in previously treated and relapsing pa
tients [8]. Fluorescence in situ hybridization (FISH)
overcomes the limitations of standard cytogenetics
and allows for the detection of numerical and struc
tural chromosomal abnormalities in both metaphase
spreads and interphase nuclei. Thus, FISH is an at
tractive alternative for evaluation of chromosomal
aberrations of MM. In contrast with the incidence of
abnormal karyotypes detected in MM with conven
tional cytogenetics, studies using FISH techniques
have identified chromosome changes in BM PCs in
more than 80% of the patients [9, 10]. Since PCs are
low in BM samples of patients with MM, we enriched
CD138+ myeloma cells by magneticactivated cell sort
ing (MACS) to improve the sensitivity of the interphase
FISH method.
Here we investigated the most prevalent genetic
changes in patients with MM. We performed inter
phase FISH using 6 probes that have been reportedly
related to MM and studied BM samples from 48 newly
diagnosed patients. We suggested that the detection
of at least these three genetic changes, 13q14 dele
tion, illegitimate IGH rearrangements, and Amp1q12,
would be helpful for patients with MM.
Molecular cytogenetic aberrations in patients
with Multiple MyeloMa studied by interphase
fluorescence in situ hybridization
L.-J. Chen, J.-Y. Li*, W. Xu, H.-R. Qiu, Y. Zhu, Y.-P. Zhang, L.-M. Duan, S.-X. Qian, H. Lu
Department of Hematology, First Affiliated Hospital of Nanjing Medical University, Jiangsu Province
Hospital Nanjing 210029, China
Background: Multiple myeloma (MM) is an incurable hematological disorder characterized by the accumulation of malignant
plasma cells within the bone marrow (BM). The clinical heterogeneity of MM is dictated by the cytogenetic aberrations present
in the clonal plasma cells (PCs). Cytogenetic studies in MM are hampered by the hypoproliferative nature of plasma cells in MM.
Therefore, fluorescence in situ hybridization (FISH) analysis combined with magnetic-activated cell sorting (MACS) is an at-
tractive alternative for evaluation of numerical and structural chromosomal changes in MM. Methods: Interphase FISH studies
with three different specific probes for the regions containing 13q14.3 (D13S319), 14q32 (IGHC/IGHV) and 1q12(CEP1 ) were
performed in 48 MM patients. Interphase FISH studies with LSI IGH/CCND1, LSI IGH/FGFR3, and LSI IGH/MAF probes
were used to detect t(11;14)(q13;q32), t(4;14)(p16;q32), and t(14;16)(q32;q23) in patients with 14q32 rearrangement. Results:
Molecular cytogenetic aberrations were found in 40 (83.3%) of the 48 MM patients. 13 patients (27.1%) simultaneously had 13q
deletion/monosomy 13 [del(13q14)], illegitimate IGH rearrangement and chromosome 1 abnormality. Del(13q14) was detected
in 21 cases (43.7%), and illegitimate IGH rearrangements in 29 (60.4%) including 6 with t(11;14) and 5 with t(4;14). None of
9 patients with illegitimate IGH rearrangements and without t(11;14) or t(4;14) we detected had t(14;16) (q32;q23). 24 of the
48 MM patients (50%) had chromosome 1 abnormalities. Among 21 patients with del(13q14), 15 patients had Amp1q12;16 had
IgH rearrangements. Whereas, among 27 cases without del(13q14), 8 had Amp1q12; 13 had IgH rearrangements. There was a
strong association between del(13q14) and Amp1q12(χ2 = 8.26, р < 0.01), and between del(13q14) and IgH rearrangement(χ2 =
3.88, p < 0.05). Conclusion: 13q deletion/monosomy 13, IGH rearrangement and chromosome 1 abnormality are frequent in MM.
They are not randomly distributed, but strongly interconnected. Interphase FISH technique combined with MACS using CD138-
specific antibody is a highly sensitive technique at detecting molecular cytogenetic aberrations in MM.
Key Words: fluorescence in situ hybridization, multiple myeloma, cytogenetic abnormality.
Received: May 9, 2007.
*Correspondence: Fax: 86-25-83781120
E-mail: lijianyonglm@medmail.com.cn
Abbreviations used: BM — bone marrow; FISH – fluorescence
in situ hybridization; MACS – magnetic-activated cell sorting;
MM – multiple myeloma; PCs – plasma cells.
Exp Oncol 2007
29, 2, 116–120
Experimental Oncology 29, 116–120, 2007 (June) 11729, 116–120, 2007 (June) 117June) 117) 117 117
Materials and Methods
Patients and BM samples. We studied 48 newly
diagnosed and untreated MM patients. BM samples of
patients with MM were obtained at diagnosis and under
informed consent, and enriched for mononuclear cells
using the Ficollgradient centrifugation method. Myeloma
cells were enriched by MACS using the CD138spe
cific monoclonal antibody BB4. CD138+ cell suspensions
fixed in methanol/acetic acid (3 : l) and stored at –20 °C.
interphase fluorescence in situ hybridization.
Slides were treated with 100 μg/ml RNAse for 30 min
at 37 ˚C followed by 2 × SSC washing for 5 min × 2
and treated with 0.005% pepsin for 5 min at 37 ˚C,
then washed twice for 5 min each in phosphate
buffered saline (PBS) and dehydrated in increasing
concentrations of ethanol (70, 85 and 100%) at room
temperature for 1 min in each solution. The slides were
denatured in a 70% formamide solution at 72 ˚C for
2 min, dehydrated in an ethanol series and airdried.
Probes (3 μl) were mixed well with hybridization buffer
(5 μl) and denatured at 72 ˚C for 5 min. Probes were
applied immediately to slides and hybridized at 37 ˚C
overnight. After hybridization, slides were washed
at 72 ˚C for 2 min in 0.4 × SSC/0.3% NP40 and in
2 × SSC/0. 1% NP40 for 1 min at room temperature.
Slides were then airdried and mounted using 10 μl
of 4’,6’diamidino2phenylindole (DAPI II) (Vysis,
Downers Grove, USA) counterstain for 1 h.
To detect a deletion on the long arm of chromo
some 13, we used D13S319 SpectrumGreen probe. To
determine the translocations involving IGH, we used the
LSI IGH/IGHV dualcolor, breakapart rearrangement
probe; the LSI IGH/CCND1 dualcolor, dualfusion
translocation probe; the LSI IGH/FGFR3 dualcolor,
dualfusion translocation probe; the LSI IGH/MAF dual
color, dualfusion translocation probe. To detect am
plifications of 1q, we used the CEP 1 SpectrumOrange
Probe at 1q12. All probes purchased from Vysis, USA.
Fluorescent images were captured with epifluores
cence microscope (Leica DRMA2, Germany) equipped
with CCD camera (AI company, UK), and using appro
priate filters. Five hundred nuclei were analyzed for each
probe. Chromosome 13 deletions were identified with
only one signal in interphase cells using D13S319 probe.
Rearrangements of the 14q32 region were determined
by means of a dualcolor FISH assay. Our strategy was
based on identifying the split and translocation of these
sequences on interphase nuclei. We first looked for
illegitimate IgH rearrangements with separate signals
using 14q32 (IGHC/IGHV) probe, which mapping at the
centromeric and telomeric borders of the IgH locus were
labeled with SpectrumGreen and SpectrumOrange, re
spectively. Then using LSI IGH/CCND1, LSI IGH/FGFR3
and LSI IGH/MAF probes, we detected fused signals in
patients with 14q32 rearrangements. Amplifications of
1q were identified with more than two signals in inter
phase cells.
BM cells samples of 8 cytogenetically normal per
sons were used as normal controls. The cutoff levels
for positive values for each probe in IFISH, which were
set at the mean of normal controls plus three standard
deviations, were as follows: del(13q14), 10%; IgH
rearrangements (IGHC/IGHV), 8.9%; t(11;14), 9.1%;
t(4;14), 5%; t(14;16) 6.5% and Amp1q12, 5%.
statistical analysis. χ2 or Fisher’s exact tests were
used for betweengroup comparison of the discrete
variables.
results
Characteristics of the patients. 48 newly diagnosed
and untreated MM patients were studied. There were
33 males and 15 females (the male to female ratio was
2.2 to 1), with a median age of 65 (range 45~77) years.
Out of 48 patients, the types of Mprotein were IgGκ in 21,
IgGλ in 11, IgAκ in 9, IgAλ in 5, and only kappa light chain
in 2 patients. According to Durie and Salmon staging [11],
9 were stage I, 16 were stage II, and 23 were stage III.
According to International Staging System [12], 22 were
stage I, 16 were stage II, and 10 were stage III.
interphase FisH studies. The patients with at least
one of the three frequent molecular cytogenetic aberra
tions, del(13q14), IGH rearrangement, and Amp1q12 were
40 (83.3%) of the 48 MM patients. Of these 48 patients,
13 (27.1%) had all three abnormalities. 21 (43.7%) showed
evidence of del(13q14). The median number of PCs with
deletions was 88% (range 27~94%). Rearrangements in
volving 14q32 region were the most common structural ab
normalities, found in 29 (60.4%) patients and 6 (20.7%) of
these corresponded to a t(11;14)(q13;q32). Another part
ner 4p16 was identified in 5 (17.2%) cases. Of 9 patients
with IGH rearrangement and without t(11;14) or t(4;14) we
detected, none had t(14;16)(q32;q23). 24 of the 48 MM
patients (50%) had abnormalities in chromosome 1 : 1
with 1 copy of 1q12, and 23 with at least 3 copies of 1q12
(Amp1q12). Among 21 patients with del(13q14), 15 had
Amp1q12, and 16 had IgH rearrangement. Whereas,
among 27 cases without del(13q14), 8 had Amp1q12, and
13 had IgH rearrangement. There was a strong association
between del(13q14) and Amp1q12 (χ2 = 8.26, p < 0.01),
and between del(13q14) and IgH rearrangement (χ2 =
3.88, p < 0.05).
The clinical data and FISH results of 48 patients
with MM were presented in Table.
Correlation of these three frequent molecular
cytogenetic aberrations with Durie and salmon
staging, international staging system and type
of paraprotein. There was no correlation between
del(13q14), illegitimate IGH rearrangement, or
Amp1q12 and Durie and Salmon staging, International
Staging System, or type of paraprotein (p > 0.05).
discussion
MM cells are characterized by high genetic instabili
ty, resulting in a complex set of numerical and struc
tural chromosomal abnormalities [13]. The detection of
genetic changes is important, not only because of their
association with clinical prognosis, but also because
they can be used as measurable targets for response
to treatment. The sensitivity of detection of genetic
changes depends on the methods used. Owing to
low ratio of PCs in BM samples and the low prolifera
118 Experimental Oncology 29, 116–120, 2007 (June)
tive activity of PCs, it is difficult to detect cytogenetic
changes by conventional Rbanding methods [14]. We
enriched CD138+ myeloma cells by MACS to improve
the sensitivity of the interphase FISH method.
Recent studies based on molecular cytogenetic
methods have shown that virtually all MM patients have
chromosomal abnormalities in their plasma cells [15].
Common genetic changes include 13q deletion/mono
somy 13, IGH rearrangement, chromosome 1 abnor
mality, hyperdiploidy, hypodiploidy, 17p13 deletion, 11q
deletion, t(11;14), t(4;14), and trisomy 12 [16–18]. In this
study, we have studied three prevalent genetic changes:
13q deletion/monosomy 13, IGH rearrangement and
Amp1q12 in 48 patients with MM by IFISH and detected
these aberrations in 83.3% of MM patients.
Deletion of 13q/monosomy 13 is common in MM.
Deletions of 13q14 have been detected in 30–50% of
MM patient samples by interphase FISH studies, which
have been seen as a powerful adverse prognostic factor
in MM patients treated with highdose chemotherapy and
stem cell support [19, 20]. In our study, FISH analysis of
the 13q14 region was performed on immunomagneti
cally selected plasma cells. We detected del(13q14) in
21 (43.7%) of the 48 MM patients with D13S319 probe.
The prevalence of the del(13q14) is similar to that most
other investigators reported using interphase FISH.
However, it is lower than that reported by FiserovaFiserova13 [13][13]
using interphase FISH on purified PCs. PCs that scored
positive with this deletion ranging from 27~94% are
similar to that reported by Chang (ranging from 11~85%)
[21]. We analyzed concurrently the correlation between
del(13q14) and Durie and Salmon staging, International
Staging System,or type of paraprotein. However, there
was no association between them.
Chromosomal abnormalities of 14q32 are the most
frequent chromosomal abnormalities, which have been
observed in about 75% of patients with a plasma cell
malignancy and have been associated in the oncogenesis
of MM [18]. Five recurrent chromosomal partners (on
cogenes) are involved in IgH translocations in MM: 4p16
(MMSET and usually FGFR3), 6p21 (cyclin D3), 11q13 (cy
clin D1), 16q23 (cMAF), and 20q11 (MAFB). Together, the
combined prevalence of these five IgH translocation part
ners is about 40% in MM, with approximately 15% 4p16,
3% 6p21, 15% 11q13, 5% 16q23, and 2% 20q11 [22, 23].
t(4;14) and t(14;16) are poor prognosis factors [24]. In our
series, IGH rearrangements were found in 29 of 48 (60.4%)
MM patients with different partner chromosomes: 11q13
(CCND1) (6/29, 20.7%), 4 p16(FGFR3)(5/29,17.2%) and
other partners(18/29,62.1%). In our study, we found that
there was no correlation between IGH rearrangement and
Durie and Salmon staging, International Staging System,
or type of paraprotein.
14q32 translocations and del(13q14) are not randomly
distributed [25]. AvetLoiseau et al. [26] defined 4 major
genetic categories of patients according to the cor
relations between them: (1) patients lacking any 14q32
abnormality (25%) and generally also lacking del(13q14);
(2) patients presenting either t(4;14) or t(14;16), almost
always associated with a del(13q14) (15% of patients);
(3) patients with other 14q32 abnormalities and present
ing del(13q14) (25%); and (4) patients with other 14q32
abnormalities but not presenting del(13q14) (35%). The
strong correlation might be the basis for a novel genetic
classification of MM because this genetic stratification is
highly associated with immunological status and clinical
presentation and with some major prognostic factors
and supports different models for MM oncogenesis.
In our study, of 48 patients with MM, the number of the
4 major genetic categories was 19 (39.6%), 5 (10.4%),
13 (27.1%), and 11 (22.9%), respectively. Among
19 without illegitimate IGH rearrangements, only 5 har
bored del(13q14). However, among 29 with illegitimate
IGH rearrangements, 16 had del(13q14). Therefore,
our study demonstrates that the 2 most frequent cy
togenetic abnormalities, 14q32 translocations and 13q
deletions, are strongly interconnected. We then analyzed
Table. The clinical data and FISH results of 48 patients with MM
No
Ag
e
(y
ea
rs
)
ag
e
D
—
S
*
IS
S
Is
ot
yp
e
D1
3S
31
9◊
14
q3
2#
(IG
HC
/IG
HV
)
IG
H/
CC
ND
1
IG
H/
FG
FR
3
IG
H/
M
AF
CE
P1
**
1 F 50 I I IgAκ no R yes no 2
2 M 56 I I κ no R yes no 2
3 M 67 II I IgAκ 89% yes R yes no 3
4 M 69 III III IgAλ no R yes no 2
5 M 72 III I IgGκ no R yes no 2
6 F 67 III II IgAλ no R yes no 2
7 M 65 II I IgGκ 64% yes R no yes 3
8 M 66 II I IgGκ 89% yes R no yes 3
9 F 56 I II IgGκ no R no yes 2
10 M 59 II II IgGλ no R no yes 2
11 M 65 III III IgGκ 92% yes R no yes 3
12 F 48 I I IgAλ no G no no 2
13 M 55 I I IgGκ no G no no 2
14 M 65 II I IgGκ no G no no 2
15 F 59 II I IgGκ 74% yes G no no 3
16 M 45 III I IgGλ no G no no 2
17 M 75 III I IgAκ no G no no 3
18 F 65 III I IgGκ no G no no 3
19 M 68 I II IgGκ no G no no 3
20 M 71 II II IgAκ no G no no 2
21 F 65 II II IgGκ 93% yes G no no 2
22 M 63 III II IgGκ no G no no 1
23 F 64 III II IgGκ no G no no 2
24 M 66 III II IgGκ no G no no 2
25 M 70 III II IgGλ no G no no 3–4
26 M 75 III II IgGλ 27% yes G no no 2
27 M 72 I III IgGλ 56% yes G no no 3
28 M 63 III III IgGκ no G no no 2
29 M 50 III III IgAκ no G no no 3
30 F 61 III III IgGκ 88% yes G no no 2
31 F 62 I I IgGλ 78% yes R no no 3
32 M 58 I I IgAλ 82% yes R no no no 3–4
33 M 51 II I IgAκ no R no no no 3
34 F 58 II I IgGκ 70% yes R no no 2
35 F 76 II I IgAλ 93% yes R no no no 3
36 F 66 III I IgAκ no R no no 3
37 F 57 III I κ 28% yes R no no 2
38 M 52 III I IgGλ 88% yes R no no 3
39 M 68 III I IgGλ 94% yes R no no no 3
40 M 70 II II IgAκ no R no no 2
41 M 74 II II IgGκ no R no no 2
42 F 71 II II IgGκ 64% yes R no no no 3
43 M 77 III II IgGκ 65% yes R no no 4
44 M 73 III II IgGλ 88% yes R no no no 3
45 M 69 II III IgGλ 90% yes R no no 3
46 M 67 II III IgGλ 94% yes R no no no 2
47 M 58 III III IgGκ no R no no no 2
48 M 68 III III IgAκ no R no no no 4
Notes: *D — S: Durie and Salmon staging; ◊percentage of interphase
nuclei with one signal and interpretation of findings where “no” indicates
absence of deletion, “yes” indicates a deletion is present; #R: 14q32 rear-
rangement; G: “germ”( without 14q32 rearrangement); **the number of
signals of chromosome 1q12.
Experimental Oncology 29, 116–120, 2007 (June) 11929, 116–120, 2007 (June) 119June) 119) 119 119
the incidence of del(13q14) in each 14q32 category of
MM. 60% (3/5) with t(4;14) displayed del(13q14).This
percentage was dramatically higher than that observed
in t(11;14) MM patients, of which only 16.7% (1/6) har
bored del(13q14) concurrently. However, there was no
significant difference between del(13q14) incidence in
t(4;14) MM patients and the incidence observed in the
overall population (60% versus 41.9%, p > 0.05).
Chromosome 1 instability is also common struc
tural abnormality, and plays an important role in the
pathogenesis of MM. Chromosome 1 aberrations are
frequently described, the short arm being preferentially
involved in deletions and the long arm in gains. It was
reported that abnormalities of chromosome 1p and 1q
were found in 36% and 40% of patients with an abnormal
karyotype [27]. J.D. Shaughnessy et al [28] performed
microarray analysis on tumor cells from 532 newly
diagnosed patients with MM. They found 70 genes,
30% mapping to chromosome 1, were linked to early
diseaserelated death. Importantly, most upregulated
genes mapped to chromosome 1q, and downregulated
genes mapped to chromosome 1p, and concluded that
altered transcriptional regulation of genes mapping to
chromosome 1 may contribute to disease progression.
In our study, we choose CEP 1 SpectrumOrange probe
to detect the chromosome 1q aberration in 48 patients
with MM. 47.9% of MM had amplification of chromo
some 1q. Amp1q12 was not significantly associated
with clinical staging and the types of paraprotein. It is
reported that gain of 1q is also associated with t(4;14) and
chromosome 13 deletion but not t(11;14). We found that
Amp1q12 was significantly associated with del(13q14),
but not with t(11;14) or t(4;14).
In summary, our study illustrates that 13q dele
tion/monosomy 13, IGH rearrangement and chromo
some 1 abnormality are frequent in MM. They are not
randomly distributed, but strongly interconnected.
The correlation of them with the clinical prognosis
should be studied further. Interphase FISH technique
combined with MACS using CD138specific antibody
is a highly sensitive technique at detecting molecular
cytogenetic aberrations and should be used in the
routine evaluation of MM.
acKnowledgeMent
This study was supported by the Foundation of
Social Development of Jiangsu Province (BS2006071)
and 135 Foundation of Jiangsu Province (RC2002044,
WK200210/135XY0201).
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МОЛЕКУЛЯРНЫЕ ЦИТОГЕНЕТИЧЕСКИЕ АБЕРРАЦИИ
У БОЛЬНЫХ МНОЖЕСТВЕННОЙ МИЕЛОМОЙ, ИЗУЧЕННЫЕ
МЕТОДОМ ИНТЕРФАЗНОЙ ФЛУОРЕСЦЕНТНОЙ
ГИБРИДИЗАЦИИ in situ situsitu
Обоснование: множественная миелома (MM) — неизлечимое гематологическое заболевание, характеризирующееся
накоплением злокачественных плазматических клеток в костном мозге (КM). Клиническая гетерогенность MM определяется
цитогенетическими аберрациями, присутствующими в клоне плазматических клеток (ПК). Цитогенетические исследования
MM осложнены гипопролиферативными особенностями ПК. В связи с этим флуоресцентная гибридизация in situ (FISH)
в комбинации с сортировкой клеток, активированных магнитными полями (MACS) представляется достойной альтернативой
методам оценки точечных и структурных изменений хромосом при MM. Методы: интерфазные исследования методом
FISH с использованием трех различных специфических зондов для участков, содержащих 13q14.3 (D13S319), 14q32
(IGHC/IGHV) и 1q12(CEP1), проводили у 48 больных с MM. Интерфазные исследования методом FISH с использованием
зондов LSI IGH/CCND1, LSI IGH/FGFR3 и LSI IGH/MAF применяли для детекции t(11;14)(q13;q32), t(4;14)(p16;q32), и
t(14;16)(q32;q23) у пациентов с перестройкой 14q32. Результаты: молекулярные цитогенетические аберрации выявляли у
40 (83,3%) из 48 больных с MM. У 13 пациентов (27,1%) одновременно определены 13q делеция/моносомия 13 [del(13q14)],
аномальная перестройка IGH и аномалия хромосомы 1. Del(13q14) детектировали в 21 случае (43,7%), а аномальные
перестройки IGH — в 29 (60,4%), в том числе у 6 пациентов с t(11;14) и 5 с t(4;14). Ни у одного из 9 больных с аномальными
перестройками IGH и без t(11;14) или t(4;14) не выявляли транслокацию t(14;16) (q32;q23). У 24 из 48 пациентов с MM
(50%) определяли аномалии хромосомы 1. В группе из 21 больных с del(13q14) в 15 случаях имелись перестройки IgH
Amp1q12;16. В то же время из 27 случаев без del(13q14) у 8 содержались Amp1q12; в 13 случаях отмечали перестройки
IgH. Выявлена взаимосвязь между del(13q14) и Amp1q12(χ2 = 8,26, p < 0,01) и между del(13q14) и перестройками IgH
(χ2 = 3,88, p < 0,05). Выводы: 13q делецию/моносомию 13, перестройку IGH и аномалию хромосомы 1 часто отмечают
при MM, причем их распределение не случайно и тесно взаимосвязано. Интерфазный анализ FISH в комбинации с
MACS с использованием CD138-специфичных антител является высокочувствительным методом детекции молекулярных
цитогенетических аберраций при MM.
Ключевые слова: флуоресцентная гибридизация in situ, множественная миелома, цитогенетическая аномалия.
Copyright © Experimental Oncology, 2007
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| id | nasplib_isofts_kiev_ua-123456789-138580 |
| institution | Digital Library of Periodicals of National Academy of Sciences of Ukraine |
| issn | 1812-9269 |
| language | English |
| last_indexed | 2025-12-07T17:15:54Z |
| publishDate | 2007 |
| publisher | Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
| record_format | dspace |
| spelling | Chen, L.J. Li, J.Y. Xu, W. Qiu, H.R. Zhu, Y. Zhang, Y.P. Duan, L.M. Qian, S.X. Lu, H. 2018-06-19T09:56:02Z 2018-06-19T09:56:02Z 2007 Molecular cytogenetic aberrations in patients with multiple myeloma studied by interphase fluorescence in situ hybridization / L.J. Chen, J.Y. Li, W. Xu, H.R. Qiu, Y. Zhu, Y.P. Zhang, L.M. Duan, S.X. Qian, H. Lu // Experimental Oncology. — 2007. — Т. 29, № 2. — С. 116–120. — Бібліогр.: 28 назв. — англ. 1812-9269 https://nasplib.isofts.kiev.ua/handle/123456789/138580 Background: Multiple myeloma (MM) is an incurable hematological disorder characterized by the accumulation of malignant plasma cells within the bone marrow (BM). The clinical heterogeneity of MM is dictated by the cytogenetic aberrations present in the clonal plasma cells (PCs). Cytogenetic studies in MM are hampered by the hypoproliferative nature of plasma cells in MM. Therefore, fluorescence in situ hybridization (FISH) analysis combined with magnetic-activated cell sorting (MACS) is an attractive alternative for evaluation of numerical and structural chromosomal changes in MM. Methods: Interphase FISH studies with three different specific probes for the regions containing 13q14.3 (D13S319), 14q32 (IGHC/IGHV) and 1q12(CEP1 ) were performed in 48 MM patients. Interphase FISH studies with LSI IGH/CCND1, LSI IGH/FGFR3, and LSI IGH/MAF probes were used to detect t(11;14)(q13;q32), t(4;14)(p16;q32), and t(14;16)(q32;q23) in patients with 14q32 rearrangement. Results: Molecular cytogenetic aberrations were found in 40 (83.3%) of the 48 MM patients. 13 patients (27.1%) simultaneously had 13q deletion/monosomy 13 [del(13q14)], illegitimate IGH rearrangement and chromosome 1 abnormality. Del(13q14) was detected in 21 cases (43.7%), and illegitimate IGH rearrangements in 29 (60.4%) including 6 with t(11;14) and 5 with t(4;14). None of 9 patients with illegitimate IGH rearrangements and without t(11;14) or t(4;14) we detected had t(14;16) (q32;q23). 24 of the 48 MM patients (50%) had chromosome 1 abnormalities. Among 21 patients with del(13q14), 15 patients had Amp1q12;16 had IgH rearrangements. Whereas, among 27 cases without del(13q14), 8 had Amp1q12; 13 had IgH rearrangements. There was a strong association between del(13q14) and Amp1q12(c2 = 8.26, р < 0.01), and between del(13q14) and IgH rearrangement(c2 = 3.88, p < 0.05). Conclusion: 13q deletion/monosomy 13, IGH rearrangement and chromosome 1 abnormality are frequent in MM. They are not randomly distributed, but strongly interconnected. Interphase FISH technique combined with MACS using CD138-specific antibody is a highly sensitive technique at detecting molecular cytogenetic aberrations in MM. Обоснование: множественная миелома (MM) — неизлечимое гематологическое заболевание, характеризирующееся
 накоплением злокачественных плазматических клеток в костном мозге (КM). Клиническая гетерогенность MM определяется
 цитогенетическими аберрациями, присутствующими в клоне плазматических клеток (ПК). Цитогенетические исследования
 MM осложнены гипопролиферативными особенностями ПК. В связи с этим флуоресцентная гибридизация in situ (FISH)
 в комбинации с сортировкой клеток, активированных магнитными полями (MACS) представляется достойной альтернативой
 методам оценки точечных и структурных изменений хромосом при MM. Методы: интерфазные исследования методом
 FISH с использованием трех различных специфических зондов для участков, содержащих 13q14.3 (D13S319), 14q32
 (IGHC/IGHV) и 1q12(CEP1), проводили у 48 больных с MM. Интерфазные исследования методом FISH с использованием
 зондов LSI IGH/CCND1, LSI IGH/FGFR3 и LSI IGH/MAF применяли для детекции t(11;14)(q13;q32), t(4;14)(p16;q32), и
 t(14;16)(q32;q23) у пациентов с перестройкой 14q32. Результаты: молекулярные цитогенетические аберрации выявляли у
 40 (83,3%) из 48 больных с MM. У 13 пациентов (27,1%) одновременно определены 13q делеция/моносомия 13 [del(13q14)],
 аномальная перестройка IGH и аномалия хромосомы 1. Del(13q14) детектировали в 21 случае (43,7%), а аномальные
 перестройки IGH — в 29 (60,4%), в том числе у 6 пациентов с t(11;14) и 5 с t(4;14). Ни у одного из 9 больных с аномальными
 перестройками IGH и без t(11;14) или t(4;14) не выявляли транслокацию t(14;16) (q32;q23). У 24 из 48 пациентов с MM
 (50%) определяли аномалии хромосомы 1. В группе из 21 больных с del(13q14) в 15 случаях имелись перестройки IgH
 Amp1q12;16. В то же время из 27 случаев без del(13q14) у 8 содержались Amp1q12; в 13 случаях отмечали перестройки
 IgH. Выявлена взаимосвязь между del(13q14) и Amp1q12(χ2
 = 8,26, p < 0,01) и между del(13q14) и перестройками IgH
 (χ2 = 3,88, p < 0,05). Выводы: 13q делецию/моносомию 13, перестройку IGH и аномалию хромосомы 1 часто отмечают
 при MM, причем их распределение не случайно и тесно взаимосвязано. Интерфазный анализ FISH в комбинации с
 MACS с использованием CD138-специфичных антител является высокочувствительным методом детекции молекулярных
 цитогенетических аберраций при MM. This study was supported by the Foundation of
 Social Development of Jiangsu Province (BS2006071)
 and 135 Foundation of Jiangsu Province (RC2002044,
 WK200210/135XY0201) en Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України Experimental Oncology Original contributions Molecular cytogenetic aberrations in patients with multiple myeloma studied by interphase fluorescence in situ hybridization Молекулярные цитогенетические аберрации у больных множественной миеломой, изученные методом интерфазной флуоресцентной гибридизации in situ Article published earlier |
| spellingShingle | Molecular cytogenetic aberrations in patients with multiple myeloma studied by interphase fluorescence in situ hybridization Chen, L.J. Li, J.Y. Xu, W. Qiu, H.R. Zhu, Y. Zhang, Y.P. Duan, L.M. Qian, S.X. Lu, H. Original contributions |
| title | Molecular cytogenetic aberrations in patients with multiple myeloma studied by interphase fluorescence in situ hybridization |
| title_alt | Молекулярные цитогенетические аберрации у больных множественной миеломой, изученные методом интерфазной флуоресцентной гибридизации in situ |
| title_full | Molecular cytogenetic aberrations in patients with multiple myeloma studied by interphase fluorescence in situ hybridization |
| title_fullStr | Molecular cytogenetic aberrations in patients with multiple myeloma studied by interphase fluorescence in situ hybridization |
| title_full_unstemmed | Molecular cytogenetic aberrations in patients with multiple myeloma studied by interphase fluorescence in situ hybridization |
| title_short | Molecular cytogenetic aberrations in patients with multiple myeloma studied by interphase fluorescence in situ hybridization |
| title_sort | molecular cytogenetic aberrations in patients with multiple myeloma studied by interphase fluorescence in situ hybridization |
| topic | Original contributions |
| topic_facet | Original contributions |
| url | https://nasplib.isofts.kiev.ua/handle/123456789/138580 |
| work_keys_str_mv | AT chenlj molecularcytogeneticaberrationsinpatientswithmultiplemyelomastudiedbyinterphasefluorescenceinsituhybridization AT lijy molecularcytogeneticaberrationsinpatientswithmultiplemyelomastudiedbyinterphasefluorescenceinsituhybridization AT xuw molecularcytogeneticaberrationsinpatientswithmultiplemyelomastudiedbyinterphasefluorescenceinsituhybridization AT qiuhr molecularcytogeneticaberrationsinpatientswithmultiplemyelomastudiedbyinterphasefluorescenceinsituhybridization AT zhuy molecularcytogeneticaberrationsinpatientswithmultiplemyelomastudiedbyinterphasefluorescenceinsituhybridization AT zhangyp molecularcytogeneticaberrationsinpatientswithmultiplemyelomastudiedbyinterphasefluorescenceinsituhybridization AT duanlm molecularcytogeneticaberrationsinpatientswithmultiplemyelomastudiedbyinterphasefluorescenceinsituhybridization AT qiansx molecularcytogeneticaberrationsinpatientswithmultiplemyelomastudiedbyinterphasefluorescenceinsituhybridization AT luh molecularcytogeneticaberrationsinpatientswithmultiplemyelomastudiedbyinterphasefluorescenceinsituhybridization AT chenlj molekulârnyecitogenetičeskieaberraciiubolʹnyhmnožestvennoimielomoiizučennyemetodominterfaznoifluorescentnoigibridizaciiinsitu AT lijy molekulârnyecitogenetičeskieaberraciiubolʹnyhmnožestvennoimielomoiizučennyemetodominterfaznoifluorescentnoigibridizaciiinsitu AT xuw molekulârnyecitogenetičeskieaberraciiubolʹnyhmnožestvennoimielomoiizučennyemetodominterfaznoifluorescentnoigibridizaciiinsitu AT qiuhr molekulârnyecitogenetičeskieaberraciiubolʹnyhmnožestvennoimielomoiizučennyemetodominterfaznoifluorescentnoigibridizaciiinsitu AT zhuy molekulârnyecitogenetičeskieaberraciiubolʹnyhmnožestvennoimielomoiizučennyemetodominterfaznoifluorescentnoigibridizaciiinsitu AT zhangyp molekulârnyecitogenetičeskieaberraciiubolʹnyhmnožestvennoimielomoiizučennyemetodominterfaznoifluorescentnoigibridizaciiinsitu AT duanlm molekulârnyecitogenetičeskieaberraciiubolʹnyhmnožestvennoimielomoiizučennyemetodominterfaznoifluorescentnoigibridizaciiinsitu AT qiansx molekulârnyecitogenetičeskieaberraciiubolʹnyhmnožestvennoimielomoiizučennyemetodominterfaznoifluorescentnoigibridizaciiinsitu AT luh molekulârnyecitogenetičeskieaberraciiubolʹnyhmnožestvennoimielomoiizučennyemetodominterfaznoifluorescentnoigibridizaciiinsitu |