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Blood, Vol. 92 No. 11 (December 1), 1998:
pp. 4269-4278
Identification of New Nonrandom Translocations in Multiple
Myeloma With Multicolor Spectral Karyotyping
By
Jeffrey R. Sawyer,
Janet L. Lukacs,
Nikhil Munshi,
K. Raman Desikan,
Seema Singhal,
Jayesh Mehta,
David Siegel,
John Shaughnessy, and
Bart Barlogie
From the Departments of Pathology, Medicine, and the Myeloma and
Transplantation Research Center, Arkansas Cancer Research Center,
University of Arkansas for Medical Sciences, Little Rock; and
Cytogenetics Laboratory, Arkansas Children's Hospital, Little Rock,
AR.
 |
ABSTRACT |
Multicolor spectral karyotyping (SKY) was performed on bone marrow
samples from 50 patients with multiple myeloma (MM) in anticipation of
discovering new previously unidentified translocations. All samples
showed complex karyotypes with chromosome aberrations which, in most
cases, were not fully characterized by G-banding. Patients of special
interest were those who showed add(14)(q32), add(8)(q24) and those
whose G-banding karyotypes showed poor chromosome morphology. Three new
recurring chromosome translocations not previously reported in MM were
identified. Two of the translocations involve recurring aberrations at
band 14q32.3, the site of the IgH locus, with different exchange
partners. The most frequently recurring rearrangement was a subtle
translocation at 14q32.3 designated as a t(14;16)(q32;q22~23), which
was identified in six patients. A second and larger translocation at
14q32, identified in two patients, was designated as a
t(9;14)(p13;q32), previously associated with Waldenstrom's
macroglobulinemia and lymphoplasmacytoid lymphoma. A third
translocation, identified in two patients, involved a whole-arm
t(6;8)(p10;q10) translocation. The SKY technique was able to refine the
designations of over 156 aberrations not fully characterized by
G-banding in this study and resolved additional chromosome aberrations
in every patient studied except two. The t(14;16)(q32;q22~23)
identified by SKY in this study suggests this may be a frequent
translocation in MM associated with complex karyotypes and disease
progression. Therefore, the SKY technique provides a useful adjunct to
routine G-banding and fluorescence in situ hybridization studies in the
cytogenetic analysis of MM.
© 1998 by The American Society of Hematology.
| |
INTRODUCTION |
MULTIPLE MYELOMA (MM) is a plasma cell
disorder characterized, at the cytogenetic level, by complex karyotypes
with frequent numerical and structural aberrations. The number of
abnormal karyotypes reported in MM varies from 20% to 60%, but is
about 40% in most published series.1,2 With conventional
chromosome banding techniques the most consistent findings in MM have
been the chromosomal aberrations add(14)(q32), t(11;14)(q13;q32),
t(8;14)(q24;q32), and chromosome 1q aberrations.3,4
Recently, several new recurring translocations in MM cell lines have
been identified, including t(4;14)(p16.3;q32.3), t(6;14)(p25;q32), and
t(14;16)(q32.3;q23).5-7 Several of these aberrations are
similar to those seen in other B-cell disorders, involving a
"promiscuous" array of exchange partners with the IgH
locus8; therefore, it remains unclear if any of these
aberrations are of primary importance in MM.
Molecular cytogenetic analysis by fluorescence in situ hybridization
(FISH) has become a standard adjunct to routine banding methods in the
clinical cytogenetics laboratory. The development of even newer
molecular cytogenetic methods such as multicolor FISH (m-FISH), and
multicolor spectral karyotyping (SKY), have also been shown to be
powerful techniques in the expansion of FISH techniques available for
the analysis of complex chromosomal rearrangements.9,10
These techniques, in conjunction with FISH probes for single genes,
hold the promise of helping bridge the gap between traditional banding
techniques and molecular genetic analysis. SKY is a molecular
cytogenetic technique that allows the simultaneous display of each
chromosome in a different color.10 This technique makes
possible the identification of chromosomal bands of unknown origin,
including translocations, insertions, complex rearrangements, and small
marker chromosomes. The SKY technique holds great promise but is
limited, in some respects, by the inability to detect chromosomal
inversions, very small deletions, insertions, or translocations.
Spectral karyotyping has recently been reported to identify hidden
chromosome abnormalities in hematological malignancies.11 In myeloma, evidence of new recurring translocations with the SKY
technique has been found.12 Two cases with a novel 14;20 translocation and three regions involving recurring translocations including 3q27~29,17q24~25 and 20q11.2~12 have been
identified.12 These results indicate that MM shows even
more karyotypic complexity than previously thought.
The application of the SKY technique as an adjunct to G-banding and
FISH studies in the clinical cytogenetics laboratory could potentially
help delineate the more complex chromosome aberrations seen in MM and
provide new clinical insights. To test the feasibility of spectral
karyotyping in a clinical setting, we have analyzed G-banded and
spectral karyotypes from the same specimens on 50 patients with MM.
| |
MATERIALS AND METHODS |
Sample selection was based on showing complex karyotypes with
chromosome aberrations which were not fully characterized by G-banding. Cases clearly showing the t(11;14)(q13;q32) were
excluded from the study because the SKY technique is not necessary to
identifiy this large rearrangement. Bone marrow of the 50 MM patients
was processed for routine chromosome studies as previously
described.13 An abnormal clone was identified as two or
more metaphases displaying either the same structural abnormality or
the same extra chromosome, or at least three cells with the same
missing chromosome. Aberrations were designated according to ISCN
(1995).14 Chromosome aberrations ascertained by SKY were
assigned breakpoints if the aberrations were identified in two or more
cells and if the comparison of DAPI banding of the same
metaphase corresponded with the G-banding of other metaphase
cells.
SKY methods.
The SKY probe mixture and hybridization reagents were prepared by
Applied Spectral Imaging (Carlsbad, CA). Briefly, the chromosome painting probes were generated as described elsewhere, by flow sorting
human chromosomes and DNA amplification using degenerate oligonucleotide primed polymerase chain reaction
(DOP-PCR).15 A combinatorial labeling of five
fluorochromes, including spectrum green, Texas red, spectrum orange,
Cy5, and Cy5.5 were used to generate the 24 colors. Slides for spectral
karyotyping were treated basically according to the manufacturer's
protocol with the probe cocktail hybridized to the slides for 2 days at
37°C. Chromosomes were counterstained with DAPI/antifade solution.
Image acquisition was performed using a SD200 Spectracube (Applied
Spectral Imaging, Inc, Carlsbad, CA) mounted on a Zeiss Axioplan II
microscope (Gottingen, Germany) using a custom designed optical filter (SKY-1; Chroma Technology, Brattleboro, VT) that allows
for simultaneous excitation of all dyes and measurement of their
emission spectra. Light travels through a Sagnac interferometer (Applied Spectral Imaging, Carlsbad, CA) in the optical
head, and an interferogram is generated at all image
points which is deduced from the optical path difference of the light
that depends on the wavelength of the emitted fluorescence. The
spectrum is recovered by Fourier transformation.16 The
spectral data are displayed by assigning red, green, or blue colors to
certain ranges of the spectrum. The red, green, blue (RGB) display
renders a similar color to chromosomes that are labeled with spectrally overlapping fluorochromes. Based on the measurement of the discrete emission spectra at all pixels of the image, the hybridization colors
are then converted to classification colors by applying an algorithm
that results in the assignment of a discrete color to all pixels with
an identical spectrum. DAPI banding images are acquired as part of the
image acquisition process and analyzed using a DAPI specific optical
filter. The DAPI images were used in conjunction with spectral
classifications and G-banding for the identification of chromosome
aberrations.
FISH.
Conventional dual-color whole-chromosome painting probes
(Vysis, Downers Grove, IL) for chromosomes 9, 14, and 16 were used according to manufacturer's protocol to confirm the translocations of
material to the add(14)(q32) chromosome (not shown). Telomere probe
14q32.3 and alpha satellite 16 (Oncor, Gaithersburg, MD) were used in
combination according to manufacturer's protocol to confirm the
reciprocal translocations t(14;16)(q32;q22~23) (not shown).
| |
RESULTS |
We examined 50 bone marrow samples by routine G-banding and reanalyzed
the same sample from each patient with spectral karyotyping for the
presence of new previously unidentified translocations (Figs 1 through 3).
Recurring nonrandom translocations identified from add(14)(q32),
add(8)(q24), or refined designations are presented in
Table 1, while the composite G-banding
karyotypes and refinements of nonclonal aberrations by spectral
karyotyping are presented in
Table
2. A total of 156 chromosome aberrations not identified by routine
G-banding were at least partially resolved with the spectral
karyotyping technique (Table 2). Among the 50 patients, numerous
translocations were identified by SKY that occurred only in one
patient; therefore, the description of results refers only to recurring
translocations identified in more than one patient.
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| Fig 1.
Spectral karyotyping of bone marrow chromosomes.
Demonstration of simultaneous hybridization of 24 combinatorially
labeled chromosome painting probes shown in display colors, aberrant
chromosomes are highlighted by arrows (A). Spectra-based classification
of the display colors shown in the same metaphase chromosomes, numbers
beside chromosomes denote origin of translocated material (B).
Karyotype of classification-colored chromosomes (C).
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| Fig 2.
Partial karyotypes from four different patients showing
recurring translocations t(14;16)(q32;q22~q23) and t(9;14)(p13;q32).
Each row represents a different patient sample with brackets within
each row indicating a different representation of the same reciprocal
translocation. Chromosomes are presented in SKY display colors (left
brackets), SKY classification colors (center brackets), and G-banding
(right brackets). Patient sample no. 8 shows translocation
t(14;16)(q32;q22~23) (A). Note the apparent breakpoint 16q22 versus
smaller der 16 in patient below. Patient sample no. 3 shows
translocation t(14;16)(q32;q22~23) (B). Note that the breakpoint
appears lower at band 16q23 in this patient. Patient samples no. 1 and
11 show the identification of a large segment designated add 14q32 by
G-banding, refined to t(9;14)(p13;q32) (C and D).
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| Fig 3.
Partial karyotypes from four different patients showing
recurring translocations t(6;8)(p10;q10) and t(1;8)(p11;q24). Each row
represents a different patient sample, with brackets within each row
indicating a different representation of the same reciprocal
translocation. Chromosomes are presented in SKY display colors (left
brackets), SKY classification colors (center brackets), and G-banding
(right brackets). Patient samples no. 33 and 39 show whole-arm
translocation t(6;8)(p10;q10) (A and B). Patient samples no. 7 and 28 show reciprocal translocation t(1;8)(p11;q24) (C and D).
|
|
Recurring aberrations of chromosome 14q32.
Seventeen patients showed aberrations of 14q32 by G-banding. Of these,
four showed translocations correctly identified by G-banding (samples
2, 4 ,13, 45). However, 8 of 50 patients identified by G-banding with
add(14)(q32) chromosomes were all refined by SKY and FISH to recurring
translocations (Table 1). Three samples with add(14)(q32)
chromosomes (samples 3, 8, 9) were identified as t(14;16)(q32;q22~23)
(Fig 2A and B) and three were designated t(8;14)(q24;q32)
translocations (samples 14, 44, 50). Two patients showing larger
add(14)(q32) translocations were identified as t(9;14)(p13;q32)
(samples 1 and 11) (Fig 2C and D). One patient designated as
t(11;14)(q13;q32) by G-banding (sample 12) was refined to a
t(3;14)(q21;q32), and an additional patient (sample 5) was identified in this study by G-banding showing this same
translocation, therefore identifying this as a recurring aberration.
Recurring aberrations involving chromosome 8.
Ten of the 50 patients showed recurring translocations involving 8q24
by G-banding, including three each with t(8;14)(q24;q32) and
t(8;22)(q24;q12), and two each with t(1;8)(p11;q24), and add(8)(q24). Of the three designated t(8;14)(q24;q32) by G-banding, two
were refined by SKY and FISH to t(14;16)(q32;q22~q23) (samples 6 and 46). Of the two patients identified as add(8)(q24) by G-banding, one
was resolved to t(8;22)(q24;q12) (sample 24) and the other to
t(6;8)(q21;q24) (sample 48), respectively. Thus, following the SKY and
FISH analysis, only one of three samples identified by G-banding showed
a t(8;14)(q24;q32), while an additional sample showed the
t(8;22)(q24;q12).
A new whole-arm t(6;8)(p10;q10) translocation was identified in two
patients (samples 29 and 39) (Fig 3A and B). One patient was identified
by G-banding (sample 39); however, the other one was identified by SKY
(sample 29). Five additional patients showed whole-arm aberrations
involving chromosome 8, including two patients with iso(8)(q), and one
each with t(8;12)(q10;q10),t(8;21)(q10;q10) and t(8;22)(q10;q10)
(Table 2).
Recurring aberrations of chromosome 1 identified by
G-banding.
Two patients showed a t(1;8)(p11;q24) translocation (samples 7 and 28)
by G-banding and both of these were confirmed by SKY analysis (Fig 3C
and D). Four patients showed recurring translocations between
chromosomes 1 and 16 designated t(1;16)(q21;q11~22).
| |
DISCUSSION |
The chromosome aberrations found in clinical cytogenetic preparations
of bone marrow samples in MM are unusual in their complexity. In many
ways, these complex karyotypes resemble those found in solid tumors,
because they combine both high numbers of numerical and structural
chromosome aberrations. Although traditional cytogenetic methods have
proven useful in providing correlations of clinical outcome, the
current banding methods for bone marrow are incapable of resolving the
more complex aberrations. The need for an adjunct technique for more
precise karyotypic interpretation of MM is clear.
In the present study, we applied G-banding and spectral karyotyping to
the same sample preparation in an attempt to extend the chromosomal
aberrations previously reported in patients with MM and to further
localize chromosomal regions that may be of importance in the etiology
and progression of this disease. Seventeen patients showed aberrations
of 14q32 by G-banding. Of these, 4 showed translocations correctly
identified by G-banding. However, 8 of the 50 specimens showed an
add(14)(q32) aberration by G-banding; of these, all were shown by SKY
to involve recurring translocations. Three samples were refined to
t(8;14)(q24;q32) and three samples were refined to
t(14;16)(q32;q22~23) (Fig 2A and B). The largest add(14)(q32)
chromosome was resolved to a t(9;14)(p13;q32) translocation in two
patients (Fig 2C and D). These results support and extend previous
studies suggesting "promiscuous" translocations to the Ig locus
at 14q32.8
The t(14;16)(q32;q22~23) translocation identified in this study
appears to involve a small range of breakpoints on chromosome 16 from
q22~q23. In two patients the breakpoint appears at 16q22 (Fig 2A),
which makes the add(14)(q32) appear larger, while in two other patients
the breakpoint appears more distal at q23 (Fig 2B) so that the
add(14)(q32) segment looks smaller. In the other two samples, the
breakpoints were unclear; therefore, we assigned the q22~23
breakpoints to chromosome 16. The SKY probe cocktails were able to
identify the add(14)(q32) material as chromosome 16 in all cases,
suggesting a reciprocal translocation, but were unable to identify any
reciprocal exchange of chromosome 14 material to the chromosome 16 (Fig
2A and B). In these cases, a FISH probe for the 14q32.3 locus in
conjunction with an alpha satellite probe to chromosome 16, was used to
determine if 14q32 was translocated to 16. Indeed, 14q32 probe signal
was found translocated to chromosome 16 by FISH, thus confirming the
reciprocal translocation in all patients (not shown). Therefore,
identification of chromosome 16 material at 14q32 by SKY ultimately led
to the complete resolution of this subtle reciprocal translocation with
the aid of standard FISH.
In one case (sample 42), a deletion of 16q22~23, suggestive of the
t(14;16)(q32;q22~23), prompted us to use conventional FISH protocols
to identify an additional patient with t(14;16)(q32;q22~23) not
detected by the SKY probes. We and others have previously reported
add(14)(q32) chromosomes in the same G-band karyotypes with deletions
of 16q22~24, suggesting that this subtle translocation is missed by
conventional techniques.13,17 It is conceivable that the
analysis of more cases with add(14)(q32) and or del(16)(q22) may show
hitherto unrecognized recurring translocations. Interestingly, a
t(14;16)(q32.3;q23) translocation has recently been identified as a
recurring aberration in MM cell lines and has been associated with
c-maf overexpression.7 The 16q23 breakpoints in these cell
lines appear to be dispersed over approximately 100 kb and appear to be
separated from c-maf by less than 500 kb. The dispersion of
breakpoints and distance from the oncogene appear to be compatible with
dysregulation of c-maf by the strong 3 IgH
enhancer.7 We believe this translocation most likely
represents the same translocation found in our patient samples.
A second recurring translocation to emerge from the SKY analysis of the
add(14)(q32) chromosomes was refined to a t(9;14)(p13;q32) translocation (Fig 2C and D). This translocation was found in two
patients. The SKY technique identified the add(14)(q32) as a
t(9;14)(p13;q32); however, the 14q32 segment that was translocated to
9p13 was again too small to be resolved by SKY. In this case, the 14q32
translocation was identified at 9p13 by the FISH probe for 14q32.3
locus. The t(9;14)(p13;q32) translocation has been associated with
lymphoplasmacytoid lymphoma, a subtype of B-cell non-Hodgkin's
lymphoma, and also associated with Waldenstrom's macroglobulinemia.
This rare lymphoma is characterized by an indolent clinical course and
followed by transformation into large cell lymphoma.18 The
translocation in this case juxtaposes the PAX-5 gene at 9p13 with the
Ig regulatory elements at 14q32 apparently deregulating PAX-5, causing
overexpression of PAX-5 mRNA.19
Translocations of 8q24 in this study were found in 13 patients by
G-banding. Band 8q24 is the locus of the c-myc proto-oncogene that is involved in the pathogenesis of a variety of B-cell
malignancies and has been reported previously in studies of MM as
t(8;14)(q24;q32) and the variant t(8;22)(q24;q12). Four of the 13 designations by G-banding were changed as a result of the SKY analysis
(Table 1). Of the two samples that could only be designated as
add(8)(q24) (samples 24 and 48) by G-banding, one of these was resolved
to be a t(8;22)(q24;q12) translocation while the other was refined to a
t(6;8)(q21;q24) translocation. Two of three patients originally designated as t(8;14)(q24;q32) (samples 6 and 46) translocations were
redesignated to t(14;16)(q32;q22~23) translocations by SKY and FISH.
Another sample was refined from a designation of ?t(2;8)(p13;q24.1) to
t(8;15)(q24.1;p21). The redesignation of different translocations involving 8q24 in this study suggests that the t(8;14)(q24;q32) in MM
may be incorrectly identified and in some cases may be the t(14;16)(q32;q22~23). This concept is supported by the findings in MM
cell lines that although IgH translocations in MM are nearly universal,
they rarely involve c-myc.20
Whole-arm chromosome translocations are a special type of rearrangement
in which chromosome arms exchange at the centromeric region. These
translocations can result in derivative chromosomes, which are
unbalanced for whole chromosome arms, resulting in partial trisomy for
one arm and partial monosomy for the other arm. When one of these
translocations occurs in poorly banded preparations with similar
centromeric indexes, these rearrangements can be incorrectly
identified. Two patients showed whole-arm t(6;8)(p10;q10) translocations. One of these patients was identified by G-banding; however, because of poor morphology and banding of chromosomes in the
other patient, the translocation was incorrectly identified (Fig 3A and
B). Five additional patients showed whole-arm aberrations involving
chromosome 8, including two patients with iso(8)(q) and one each with
t(8;12)(q10;q10),t(8;21)(q10;q10) and t(8;22)(q10;q10). Interestingly, in each of these eight cases the short arm of chromosome 8 was lost, suggesting the possibility of the loss of a putative tumor
suppressor gene on 8p in the progression of chromosome aberrations in
MM.
Chromosomal studies in MM point to the gradual accumulation of numerous
chromosome aberrations, especially structural rearrangements of
chromosome 1. Although large translocations involving chromosome 1 breakpoints at 1q21 have been identified in MM by routine banding, the
recent cloning of a novel gene (BCL9) involving a t(1;14)(q21;q32) suggests it may play a role in the progression of B-cell
malignancies.20 The function of the BCL9 gene is not yet
known, yet some translocations of 1q21 result in overexpression of
BCL9.21 We identified one patient in this study with
t(1;14)(q21;q32) and also identified four additional patients with 1q21
breakpoints involving t(1;16)(q21;q11~22), suggesting this recurring
translocation may play a role in the progression of MM. In addition to
1q aberrations, a new recurring translocation t(1;8)(p11;q24) was
identified by G-banding and confirmed by SKY. The 8q24 material
translocated to 1p11 was the smallest reciprocal exchange of
chromosomal material identified by SKY in this study (Fig 3C and D).
Although spectral karyotyping identified additional rearrangements in
all cases except two, the technique does have limitations. The main
drawback appears to be the limits of resolution of the painting probe
cocktails, which are reported to be between 500 and 1,500 kb.10 Therefore, the technique is unable to completely resolve the very subtle translocations of less than 500 kb. The subtle
translocations of 14q32 to the exchange partners in the t(14;16)(q32;q22~23) and t(9;14)(p13;q32) translocations were both
below the resolving power of SKY. To completely resolve these translocations, we applied a FISH probe for the telomere of 14q32. However, in most cases, the spectral karyotyping refined the G-band by
identifying several of the derivative or add chromosomes. It appears
clear that multiple adjunct techniques to G-banding, including both
FISH and SKY, are necessary to resolve the complex karyotypes of MM.
The search for a primary cytogenetic event in MM has proven difficult
because, by the very nature of the disease process, most karyotypes
have already evolved by the time of diagnosis. As in other tumor types,
numerous cytogenetic studies indicate that more advanced disease is
associated with higher frequencies of chromosome
aberrations.3,22,23 Recently, the association of poor
prognosis with the presence of the specific chromosome aberrations of
11q and monosomy and/or deletion 13q has been
reported.24,25 It is interesting to note that all patients
in this study who showed t(14;16)(q32;q22~23) also showed the poor
prognostic indicator monosomy 13. Clearly a larger study is needed to
correlate cytogenetic findings of patient samples with other prognostic
indicators since this study of karyotypes had a selection bias. The
bias in this study was toward complex karyotypes and aberrations of
add(14)(q32). Therefore, the true frequency of the new or redesignated
translocations and/or associations with poor prognostic
indicators awaits to be ascertained in a larger study. However, because
6 of 50 patients with complex karyotypes showed t(14;16)(q32;q22~23),
this suggests that it may be a frequently occurring translocation
overlooked by banding techniques. Multicolor spectral karyotyping
appears to be an important adjunct to routine G-banding in the clinical cytogenetic analysis of MM.
| |
FOOTNOTES |
Submitted May 18, 1998;
accepted July 17, 1998.
Supported in part by CA55819 from the National Cancer Institute.
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 Jeffrey R. Sawyer, PhD, Cytogenetics
Laboratory, Arkansas Children's Hospital, 800 Marshall St, Little
Rock, AR 72202.
| |
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Abstract
Introduction
