|
|
 Previous Article | Table of Contents | Next Article 
Blood, Vol. 92 No. 3 (August 1), 1998:
pp. 802-809
Presence of a p53 Gene Deletion in Patients With Multiple Myeloma
Predicts for Short Survival After Conventional-Dose Chemotherapy
By
Johannes Drach,
Jutta Ackermann,
Elke Fritz,
Elisabeth Krömer,
Rudolf Schuster,
Heinz Gisslinger,
Maria DeSantis,
Niklas Zojer,
Michael Fiegl,
Sebastian Roka,
Judith Schuster,
Renate Heinz,
Heinz Ludwig, and
Heinz Huber
From the First Department of Internal Medicine, the Division of
Clinical Oncology, and the Division of Hematology and Hemostesiology,
University of Vienna, Vienna; First Department of Internal Medicine
with Medical Oncology, Wilhelminenspital, Vienna; Ludwig
Boltzmann-Institute for Leukemia Research and Hematology, and Third
Department of Internal Medicine, Hanusch-Krankenhaus, Vienna; and
Ludwig Boltzmann-Institute for Applied Cancer Research, Kaiser Franz
Josef-Spital, Vienna, Austria.
 |
ABSTRACT |
In multiple myeloma (MM), previous studies showed that mutations of
the p53 gene are rare events in patients with newly diagnosed disease,
but it is not known whether deletions of p53 are of any significance in
MM. To address this question, we used interphase fluorescence in situ
hybridization (FISH) with a DNA probe specific for the p53 locus at
17p13 and investigated bone marrow plasma cells from 72 patients with
MM (59 patients = 81.9% before therapy). By FISH, deletions of
p53, which were found to be predominantly monoallelic, were detected in
32.8% and 54.5% of patients with newly diagnosed and relapsed MM,
respectively. Karyotypes from six of the patients with a p53 deletion
by FISH showed a structural abnormality of 17p in only one of them.
Additional FISH studies including a distal-17p probe (specific for the
D17S34 locus) provided evidence for an interstitial deletion on
17p resulting in loss of p53 hybridization signals in myeloma cells.
Among all 59 patients with newly diagnosed MM, presence of a p53
deletion was associated with stage III (P = .054), but not
with other laboratory and clinical parameters. Patients with a p53
deletion had significantly shorter survival time compared with those
without a deletion, both from the time of diagnosis (median 13.9 v 38.7 months; P < .0001) and from the time of
initiation of induction treatment consisting of conventional dose
chemotherapy (median 15.9 months v median not reached at 38 months; P < .0002). On stepwise multivariate regression
analysis, presence of a p53 deletion was the most significant independent parameter predicting for shortened survival
(P = .002). We conclude that a p53 gene deletion, which can
be identified by interphase FISH in almost a third of patients with
newly diagnosed MM, is a novel prognostic factor predicting for short
survival of MM patients treated with conventional-dose chemotherapy.
© 1998 by The American Society of Hematology.
| |
INTRODUCTION |
THE p53 TUMOR suppressor gene, which maps
to 17p13,1 has been shown to be implicated in the control
of normal cellular proliferation, differentiation, and
apoptosis.2 Inactivation of p53 due to mutation or allelic
loss has been observed in many solid tumors, and results suggested a
relation between presence of a p53 mutation and tumor development or
progression.3,4 In addition, alterations of the p53 gene
have been reported to be of prognostic relevance in non-small cell
lung cancer5 as well as in breast cancer.6 In
hematological malignancies, mutations of p53 generally occur at a lower
frequency compared with solid tumors,7 but when present
they appear to identify prognostically relevant subgroups of patients
with acute myelogenous leukemia, myelodysplastic syndromes, and
aggressive non-Hodgkin's lymphomas.8,9 In contrast,
multiple myeloma (MM) is one of the few neoplasms in which p53
mutations are very rare at the time of diagnosis. Overall, p53
mutations were found to occur in fewer than 20% of patients with MM,
which usually had advanced and aggressive forms of the disease
including plasma cell leukemia.10-15 It was concluded from
these studies that p53 mutations represent a late event in the
progression of MM and have only limited value as a prognostic factor in
MM.
p53 function may also be compromised by presence of a gene deletion,
which has been shown in a recent study of patients with chronic
lymphocytic leukemia (CLL).16 In this B-cell malignancy, deletions of p53 were predictive for nonresponse to purine-analogs like
fludarabine and for short survival. In MM, chromosomal abnormalities leading to loss of 17p were only infrequently reported in conventional cytogenetic studies of MM.17-22 However, cytogenetic
studies by means of metaphase analysis are limited in MM because of the
low proliferative capacity of myelomatous plasma cells in vitro. We and
others have previously shown that detection of chromosomal abnormalities in MM is improved by use of interphase fluorescence in
situ hybridization (FISH), and that chromosomal aneuploidy is present
in the majority of patients with MM.23-26
Thus, the aims of the present investigation were twofold: First,
because deletions of 17p13 have not yet been studied systematically in
MM, we investigated the incidence of p53 deletions using interphase FISH with a p53-specific DNA probe. Second, we addressed the question whether presence of a p53 deletion was of any clinical and prognostic significance in MM.
| |
MATERIALS AND METHODS |
Patients.
Seventy-four bone marrow (BM) samples from 72 consecutive, nonselected
patients with MM (median age 63 years, range 34 to 87) were studied.
There were 59 patients at diagnosis, 4 patients during induction
chemotherapy, and 9 patients at relapse; 2 patients were studied both
at initial presentation and at relapse. Main characteristics of
patients are summarized in Table 1. When
patients had symptomatic and/or progressive disease, they
received conventional-dose chemotherapy as induction treatment:
Melphalan-based regimens (melphalan/prednisone,
vincristine/melphalan/cyclophosphamide/prednisone ± carmustine) were administered in 36 patients (5 of them concomitantly received interferon- ), 5 patients were treated with VAD
(vincristine/doxorubicin/dexamethasone), and 1 patient received
high-dose glucocorticoids. Response to treatment was defined as a
sustained decrease (for longer than 4 weeks) of the paraprotein-level
to less than 50% of the pretreatment value; in addition, achievement
of a response required normalization of a preexisting hypercalcemia and
no increase in the number and/or size of lytic bone
lesions.27 One patient not responding to melphalan/prednisone was subsequently treated with high-dose melphalan (140 mg/m2) followed by autologous stem cell support.
Cells.
BM aspirates were obtained from the posterior iliac crest or sternum
during standard diagnostic procedures and were collected in a
heparinized syringe. Informed consent according to institutional guidelines was obtained for the use of an aliquot of the samples for
research purposes. After dilution with phosphate-buffered saline (PBS),
mononuclear BM cells were separated by density gradient centrifugation
over Ficoll-Hypaque (density = 1.077; Sigma Inc, St Louis, MO).
Mononuclear cells were washed twice with PBS, treated with Carnoy's
fixative (methanol/glacial acetic acid 3:1 [vol/vol]), and stored at
 20°C or 80°C.
Specimens used as controls consisted of peripheral blood (PB) (n = 4)
and BM samples (n = 9) from healthy individuals. Reactive plasma
cells were obtained from the PB of a patient with severe sepsis
(nucleated PB cells consisted of 40% plasma cells).
Slides with normal metaphases derived from
phytohemagglutinin-stimulated lymphocytes were obtained from Vysis, Inc
(Downers Grove, IL).
Interphase FISH studies.
DNA probes specific for the p53-locus on 17p13 (directly conjugated
with SPECTRUM-Orange), for the Rb-1 locus on 13q14 (directly conjugated
with SPECTRUM-Orange), and for the centromeric region of
chromosome 17 (directly conjugated with SPECTRUM-Green) were purchased
from Vysis, Inc. A probe hybridizing to the D17S34 locus (labeled with digoxigenin), which maps distal of p53 on
17p,28 was obtained from Oncor (Gaithersburg, MD). An
anti-digoxigenin antibody tagged with rhodamine (Oncor) was used as
secondary reagent to visualize the hybridized D17S34 probe.
Hybridization was performed as detailed in a previous
report.29 To control for sufficient hybridization
conditions, experiments were always performed as dual-color
hybridizations combining the chromosome 17-centromeric probe with
either the p53 or the D17S34 probe. Since none of the myeloma
specimens was characterized by loss of the chromosome 17 centromere,
presence of  2 signals with this probe in more than 90% of nuclei was
considered as evidence for high hybridization efficiency. Only slides
fulfilling these criteria were scored, and at least 200 cells with the
appearance of plasma cells were evaluated.
Images were captured using a cooled charge coupled device (CCD) camera
(Photometrics, Tucson, AZ) mounted on a Zeiss Axioplan-2 immunofluorescence microscope (Zeiss, Jena, Germany) and linked to an
Apple Macintosh computer (Apple Comp Corp, Cuperdino, CA). Prints were obtained with a Phaser 440 Tektronix color printer (Tektronix, Inc, Wilsonville, OR).
Metaphase cytogenetics.
Mononuclear cells after Ficoll-Hypaque density separation were washed
twice and subsequently cultured at 2 × 106/mL in
-MEM:McCoy's 5A (1:1, vol/vol) or RPMI1640 medium supplemented with
20% heat-inactivated fetal calf serum. Growth factors
(granulocyte-macrophage colony-stimulating factor, 100 U/mL;
interleukin-6 [IL-6], 250 U/mL; IL-10, 25 U/mL; 10% B- and T-cell
growth supplement, obtained from Origen [Origen Inc, Rockville,
MD]), either alone or in combination, were added to
parallel cultures. Harvesting and spreading of metaphases on slides was
performed using standard techniques, followed by the tristain protocol
established by Schweizer.30,31 Metaphases were analyzed
using the semi-automated Genevision 221 karyotyping system (Applied
Imaging, Carlsbad, CA). Chromosomal aberrations were
defined and described according to the International System for
Cytogenetic Nomenclature.32
Statistical analysis.
Statistical evaluation of results included Fisher's exact test,
 2-test, t-test, and the nonparametric
Kruskal-Wallis test. Odds ratios were determined according to
Mantel-Haenszel. Kendall's tau coefficients were used in testing
correlations. Survival time, measured both from the date of diagnosis
and the date of start of induction treatment, was calculated using
Kaplan-Meier estimates. Differences between survival curves were
analyzed by means of Breslow and Mantel-Cox tests. Multivariate
analysis of survival time data was performed using the proportional
hazards regression model of Cox. Stepwise evaluation of maximum partial
likelihood ratio was used to identify prognostic factors.
| |
RESULTS |
Control hybridizations.
To establish the cut-off level for presence of a p53 deletion by
interphase FISH, hybridizations were performed with PB (n = 9) and BM
specimens (n = 4) from healthy individuals. As with the myeloma
specimens, simultaneous hybridizations with probes specific for the
chromosome 17 centromere and the p53 locus were performed (Fig
1). In normal specimens, we observed fewer
than two hybridization signals per nucleus with the p53 probe in 3.24% ± 1.79% (mean ± standard deviation [SD]) of
nuclei. Of note, there was no significant difference between normal PB
and BM samples. In addition, similar results were obtained with
reactive plasma cells (PB plasmocytosis in a patient with severe
sepsis) exhibiting one p53 hybridization signal in 3.4% of cells (407 cells evaluated). Thus, the cut-off level for the presence of a p53
deletion was set at 8.6% (mean + 3 SD of the frequency of control
cells with only one p53 hybridization signal).
View larger version (99K):
[in this window]
[in a new window]
| Fig 1.
FISH analysis of the p53 gene at 17p13 using a specific
DNA probe (red fluorescent signals), hybridized simultaneously with a
chromosome 17-centromeric probe (green fluorescent signals). Probes
were applied to normal, phytohemagglutinin-stimulated lymphocytes and a
metaphase spread as well as an interphase nucleus showing a normal
hybridization pattern are displayed.
|
|
Deletions of p53 in MM by interphase FISH.
In 25 of 74 BM samples (33.8%) from patients with MM, interphase FISH
analysis of plasma cells provided evidence for a p53 gene deletion (Fig
2). Among 59 patients with newly diagnosed MM, a deletion of p53 was detected in 19 of them (32.8%); at relapse, a p53 deletion was observed in 6 of 11 patients (54.5%). None of the 4 patients studied during induction chemotherapy exhibited a p53
deletion. Two patients, who had normal findings for p53 by FISH at
diagnosis, were again studied at relapse, and a deletion of p53 was
detected in one of them. The percentage of plasma cells exhibiting a
p53 deletion ranged between 17.8% and 95.0% (median, 49.1%). In 17 of the 25 patients, deletions of p53 were monoallelic, whereas in 7 patients loss of both p53 alleles was observed in 20% to 40% of the
deleted plasma cell population. In one patient with relapsed MM, a
biallelic deletion of p53 was found.
View larger version (103K):
[in this window]
[in a new window]
| Fig 2.
Interphase FISH analysis of the p53 gene in MM: (A)
Plasma cell from a patient without p53 deletion: Two hybridization
signals with both probes (chromosome 17 centromere, green signals; p53, red signals) can be recognized. (B) Plasma cells from patient 3/FJ
(Table 2) exhibiting a monoallelic deletion of p53 (probes as in A).
(C) Interphase cell of patient 2/NN (compare Table 2: trisomy 17 by
metaphase cytogenetics) hybridized with 3 probes: Chromosome 17 centromere (labeled with SPECTRUM-Green; large green signals), p53
(labeled with SPECTRUM-Orange; red signal), and distal 17p
(D17S34 locus, labeled with digoxigenin and visualized with
anti-digoxigenin-fluorescein isothiocyanate; small green signals).
Presence of three signals for chromosome 17 centromere and
D17S34, but only one signal for p53 indicating an interstitial deletion on 17p involving the p53 locus.
|
|
Gain of signals with the chromosome 17 centromeric probe was observed
in 10 patients (13.3%), and in three of these patients, a deletion of
p53 was found. Of note, also in these patients fewer than two
hybridization signals with the p53-specific probe were observed
(compare Fig 2C), indicating the presence of a true deletion and not
just relative loss of p53. In the remaining 7 patients, gain of
chromosome 17 centromere was paralleled by a gain of hybridization domains for the p53 gene.
Comparison of metaphase cytogenetics and interphase FISH.
Conventional cytogenetic studies were performed in 23 patients, and
clonal chromosomal abnormalities were detected in 10 patients (43.5%).
In 7 of these 23 patients, interphase FISH provided evidence for a p53
deletion in plasma cells. By metaphase cytogenetics, however,
chromosome 17 was found to be structurally abnormal in only one patient
(Table 2, patient 1/GN): One chromosome 17 was found to be derivative with loss of material from both arms, and on
the second chromosome 17 additional material was found distal of band
17p13 (add17p13). In patient 2/NN, metaphase analysis indicated
presence of trisomy 17 (without structural abnormalities involving
chromosome 17), which corresponds to the finding of three signals by
FISH with the chromosome 17 centromeric probe; however, only one p53
signal was observed by interphase FISH. In four patients, normal
results for chromosome 17 were obtained by metaphase analysis, and in
patient 7, only diploid metaphases were found.
Interphase FISH analysis of the D17S34 locus in MM.
Because interphase FISH, but not metaphase chromosome analysis,
indicated loss of material from 17p, we performed additional hybridization studies using a distal 17p DNA probe specific for the
D17S34 locus. D17S34 represents the most distal
genetically mapped region of the chromosome 17p arm.27 In
normal specimens, 96.7% ± 0.4% of nuclei showed two hybridization
signals for D17S34, and only one hybridization domain was
observed in 2.9% ± 0.5% of cells (cutoff level for loss of
D17S34: 4.4%). All 25 myeloma patients, who were found to have
a p53 gene deletion by FISH, were studied with the D17S34 probe
by interphase FISH (simultaneous hybridizations with the chromosome 17 centromeric probe). In only 3 of these 25 patients, a deletion of
D17S34 was observed by FISH (Table
3), and the concomitant loss of
hybridization signals for both p53 and D17S34 strongly suggests
a deletion of the 17p arm. However, in all other patients (deletion of
the p53 gene, but presence of the D17S34 locus) an interstitial
deletion involving 17p13 should be the abnormality leading to the
observed loss of p53 hybridization signals. To test this hypothesis, we
performed simultaneous hybridizations with three probes (chromosome
17-centromere, p53, D17S34) to interphase nuclei of patient
2/NN (trisomy 17 by metaphase cytogenetics, but deletion of p53 by
interphase FISH; compare Table 2): As illustrated in Fig 2C, a normal
hybridization pattern with presence of hybridization signals for all
three probes was observed for only one chromosome 17, whereas both
remaining chromosomes 17 were characterized by loss of the p53 locus in the presence of hybridization signals for chromosome 17-centromere and
D17S34. Taken together, these results indicate that deletion of
the p53 gene in MM is mainly due to an interstitial deletion of a
presumably narrow chromosomal region on 17p, and that this abnormality
remains unrecognizable by metaphase chromosome analysis.
Correlation of p53 deletions with laboratory and clinical findings.
Analyzing data from all 59 patients with newly diagnosed MM, we
addressed the question whether or not the p53 status by FISH was
correlated with clinical and major prognostic parameters. Regarding the
Durie & Salmon stage, patients with a p53 deletion were predominantly
at stage III (p53 deletion in 38.5% of stage III patients v
12.5% of patients at stages I and II; P = .054). However,
there was no significant correlation of p53 status with sex, age, type
of the paraprotein, serum creatinine, hemoglobin, platelet count, serum
lactat dehydrogenase-level, C-reactive protein, or beta-2
microglobulin (B2M). In 27 of the patients with newly diagnosed MM, results from interphase FISH studies of chromosomal region 13q14 were available. Loss of 13q14 was observed in 15 patients
(55.6%); however, we did not observe an association between deletion
of p53 and loss of 13q14 (contingency correlation r = .246, P < .1).
Figure 3 shows the survival probabilities
from the time of diagnosis of all 59 previously untreated patients:
Patients with and without p53 deletions had significantly different
overall survival times (median 13.9 months and 38.7 months,
respectively; P < .0001). Forty-two patients received
induction treatment with conventional-dose chemotherapy. Response to
treatment was observed in 26 patients (61.9%). Among the 14 patients
with a p53 deletion by FISH, 42.9% responded compared with 71.4% of
patients without p53 deletion (P = .078). However, survival
time from the time of initiation of induction chemotherapy was
significantly shorter for patients with a p53 deletion (Fig
4; P < .0002). Among patients with a p53 deletion, only one patient survived longer than 30 months:
This patient was a 36-year-old woman who did not respond to
melphalan/prednisone, but achieved a partial remission after high-dose
melphalan and autologous PB stem cell support.
View larger version (16K):
[in this window]
[in a new window]
| Fig 3.
Survival probabilities from the time of diagnosis in 59 patients with newly diagnosed MM. The solid line represents patients with a p53 deletion by FISH (n = 19), the dotted line those without a p53 deletion (n = 40). The median survival times of both groups are significantly different (P < .0001).
|
|
View larger version (15K):
[in this window]
[in a new window]
| Fig 4.
Survival probabilities from the time of start of
induction therapy (conventional-dose chemotherapy) in 42 patients with
newly diagnosed MM. Patients with a p53 deletion (n = 14; solid
line) have a significantly shorter survival time compared with MM
patients without a p53 deletion (n = 28; dotted line)
(P < .0002).
|
|
When comparing noncensored survival data from 52 myeloma patients who
had either been observed for more than 12 months or had died within the
first year after diagnosis, deletion of p53 was found to be associated
with a more than fivefold risk to die within 12 months from diagnosis,
as compared with patients with normal findings for p53 (Table
4).
Univariate linear regression identified deletion of p53, elevated
serum-creatinine, elevated B2M, age over 65, stage III, and
a high percentage of BM plasma cells as prognostic factors for
shortened survival. On stepwise multivariate regression analysis, presence of a p53 deletion proved to be the best prognostic factor: It
contributed more than twice as much to accurate prediction of survival
than advanced stage, which remained the second independent prognostic
factor (Table 5).
| |
DISCUSSION |
In this study we report that deletions of the p53 gene are detectable
by interphase FISH in a significant proportion of patients with MM.
Specifically, plasma cells from 32.8% of patients with newly diagnosed
MM carry a p53 deletion, and the incidence of this abnormality
increases to 54.5% in patients with relapsed MM. Our results indicate
that deletions of 17p involving the p53 gene locus are much more common
than previously assumed based on findings by metaphase cytogenetics.
Evidence that 17p may be deleted in MM was also obtained in a recent
molecular cytogenetic study of 13 MM cell lines and 8 tumor specimens
including 5 cases of plasma cell leukemia: By means of comparative
genomic hybridization, underrepresentation of region 17p11.2-p13 was a
recurrent finding.33 The higher frequency of p53 gene
deletions by FISH compared with banding analysis can only in part be
explained by the fact that metaphase cytogenetics remains normal or
noninformative in the majority of patients with newly diagnosed MM
despite the finding of chromosomal aneuploidy by interphase
FISH.23 Of note, we also observed p53 deletions by FISH in
cases with abnormal cytogenetics, but apparently normal findings for
chromosome 17 or 17p. Although it may be difficult to identify bands on
metaphase chromosomes from lymphoid malignancies,34 the
most likely explanation for the failure of detecting this deletion by
banding studies is the presence of a physical deletion of 17p on the
submicroscopical level. By additional hybridization experiments we have
obtained evidence that the D17S34 locus distal on 17p is
present in all but three cases with a p53 deletion by FISH. Thus, it is
our conclusion that loss of p53 hybridization signals is predominantly
due to an interstitial deletion that presumably is too small to be
detected on metaphase chromosomes. In agreement with this conclusion,
there is increasing evidence that FISH is a more sensitive method than banding analysis to detect deletions of narrow chromosomal regions. For
example, FISH was shown to identify deletions of 9p involving the
CDKN2 gene (p16INK4a/MTS1) in acute
lymphoblastic leukemia,35,36 and of 12p in acute
leukemias,37-41 both in the absence of microscopically
visible deletions on metaphase chromosomes.
Our findings by FISH show that in the majority of patients with MM, p53
deletions are monoallelic. Although we do not have data on p53
mutations in our group of patients, we consider the coincidence of p53
deletions and mutations as a rare event in newly diagnosed MM because
of the low reported frequency of p53 mutations at this stage of the
disease.10-15 This is in contrast to observations in many
other solid and hematological malignancies, where inactivation of p53
most commonly occurs through point mutation in one p53 allele, and
deletion of the second one.7 Currently, we cannot answer
the question whether p53 function in myeloma cells is compromised
already by presence of a monoallelic deletion or by any additional
mechanism. For example, inactivation of p53 may occur by interaction
with other cellular proteins, particularly the murine double minute 2 (MDM2) protein.42 In MM cell lines, overexpression of MDM2
as well as binding of MDM2 to p53 has recently been
shown.43 However, it is not known if this is also true for
myeloma cells isolated directly from patients, and if suppression of
p53 function by MDM2 may be facilitated in case of a p53 gene deletion.
With respect to clinical correlations, our study shows that presence of
a p53 deletion in plasma cells from patients with MM was associated
with significantly shortened survival. This specific chromosomal
abnormality proved to be the most powerful prognostic factor of all
variables investigated. Stepwise Cox analysis revealed two independent
prognostic factors for shortened survival, namely deletion of p53 and
advanced stage. Other known indicators of poor prognosis, like elevated
B2M, impaired renal function, and advanced age, could not
improve the prognostic power of these two factors.
The main reason for short survival of myeloma patients with a p53
deletion by FISH was poor response to chemotherapy, which in this group
of patients was administered at conventional doses. The outcome was
independent of the type of primary treatment whether it was
melphalan-based or VAD. The association of a p53 deletion with poor response is reminiscent of what has been observed in patients
with B-CLL in whom presence of a p53 deletion was correlated with
nonresponse to otherwise very effective purine-analogs like fludarabine.16 Obviously, patients with p53 deletions show
poor response to various unrelated chemotherapeutic agents. Because many cytotoxic drugs act through induction of apoptosis, and apoptosis requires a functional p53, it has been suggested that in tumor cells
with impaired p53 function, apoptosis may not occur leading to
resistance to chemotherapeutic agents.44 Alternatively, an altered p53 gene may lose its function as `guardian of the
genome,'45,46 and, as a consequence, complex cytogenetic
abnomalities may develop. These genetic changes could then be the true
reason for resistance to treatment. Indeed, although karyotypes
obtained from MM patients are usually complex, some specific
chromosomal abnormalities were recently shown to be indicative for
shortened event-free and overall survival, even after an intensive
therapeutic approach including two autotransplants: Partial or complete
loss of chromosome 13, aberrations involving 11q, and presence of
translocations were identified as such unfavorable cytogenetic
features.47,48 With respect to loss of 13q, which was found
in 15 of 27 newly diagnosed patients of this series, we did not observe
a correlation with p53 deletions. However, this does not exclude
presence of any other unfavorable cytogenetic abnormality present in
myeloma patients with a p53 gene deletion, but a comprehensive FISH
analysis of prognostically relevant chromosomal regions in these
patients is in progress.
We conclude that in contrast to p53 mutations, allelic loss of p53 is
not uncommon in newly diagnosed MM and is predictive for short survival
of patients treated with conventional-dose chemotherapy. It remains to
be determined whether or not the unfavorable outcome of myeloma
patients with a p53 deletion can be improved by high-dose treatment
including autologous stem cell support. In case of prolonged survival
of these high-risk patients after intensive therapy, molecular
cytogenetics performed at diagnosis could contribute to identification
of an unfavorable group of MM patients benefiting significantly from a
risk-adapted therapeutic approach.
| |
FOOTNOTES |
Submitted October 30, 1997;
accepted April 6, 1998.
Supported by grants from the Austrian Fonds zur Förderung der
wissenschaftlichen Forschung (P-10893-MED, P-12432-MED) and the
Austrian National Bank (Jubiläumsfonds 5839).
Address reprint requests to Johannes Drach, MD, University of Vienna,
First Department of Internal Medicine, Division of Clinical Oncology,
Währinger Gürtel 18-20, A-1090 Vienna, Austria; e-mail: johannes.drach{at}akh-wien.ac.at.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
REFERENCES |
1.
Isobe M,
Emmanuel B,
Givol D,
Oren M,
Croce C:
Localization of gene for human p53 tumour antigen to band 17p13.
Nature
320:84,
1986[Medline]
[Order article via Infotrieve]
2.
Vogelstein B,
Kinzler KW:
p53 function and dysfunction.
Cell
70:523,
1992[Medline]
[Order article via Infotrieve]
3.
Hollstein M,
Sidransky D,
Vogelstein B,
Harris CC:
P53 mutations in human cancers.
Science
253:49,
1991[Abstract/Free Full Text]
4.
Soussi T,
Legros Y,
Lubin R,
Ory K,
Schlichtholz B:
Multifactorial analysis of p53 alteration in human cancer: A review.
Int J Cancer
57:1,
1994[Medline]
[Order article via Infotrieve]
5.
Horio Y,
Takahashi T,
Kuroishi T,
Hibi K,
Suyama M,
Nimi T,
Shimokata K,
Yamakawa K,
Nakamura Y,
Ueda R,
:
Prognostic significance of p53 mutations and 3p deletions in primary resected non-small cell lung cancer.
Cancer Res
53:1,
1993[Abstract/Free Full Text]
6.
Thorlacius S,
Borresen AL,
Eyfjord JE:
Somatic p53 mutations in human breast carcinomas in an Icelandic population: A prognostic factor.
Cancer Res
53:1637,
1993[Abstract/Free Full Text]
7.
Preudhomme C,
Fenaux P:
The clinical significance of mutations of the p53 tumour suppressor gene in haematological malignancies.
Br J Haematol
98:502,
1997[Medline]
[Order article via Infotrieve]
8.
Lai JL,
Preudhomme C,
Zandecki M,
Flactif M,
Vanrumbeke M,
Wattel E,
Fenaux P:
Myelodysplastic syndromes and acute myeloid leukemia with 17p deletion. An entity characterized by specific dysgranulopoiesis and a high incidence of P53 mutations.
Leukemia
9:370,
1995[Medline]
[Order article via Infotrieve]
9.
Ichikawa A,
Kinoshita T,
Watanabe T,
Kato H,
Nagai H,
Tsushita K,
Saito H,
Hotta T:
Mutations of the p53 gene as a prognostic factor in aggressive B-cell lymphoma.
N Engl J Med
337:529,
1997[Abstract/Free Full Text]
10.
Portier M,
Moles J-P,
Mazars G-R,
Jeanteur P,
Bataille R,
Klein B,
Theillet C:
p53 and RAS gene mutations in multiple myeloma.
Oncogene
7:2539,
1992[Medline]
[Order article via Infotrieve]
11.
Preudhomme C,
Facon T,
Zandecki M,
Vanrumbeke M,
Lai JL,
Nataf E,
Loucheux-Lefebvre MH,
Kerckaert JP,
Fenaux P:
Rare occurrence of P53 gene mutations in multiple myeloma.
Br J Haematol
81:440,
1992[Medline]
[Order article via Infotrieve]
12.
Willems PMW,
Kuypers A,
Meijerink J,
Holdrinet R,
Mensink E:
Sporadic mutations of the p53 gene in multiple myeloma and no evidence for germline mutations in three familial myeloma pedigrees.
Leukemia
7:986,
1993[Medline]
[Order article via Infotrieve]
13.
Neri A,
Baldini L,
Trecca D,
Cro L,
Polli E,
Maiolo AT:
p53 gene mutations in multiple myeloma are associated with advanced forms of malignancy.
Blood
81:128,
1993[Abstract/Free Full Text]
14.
Corradini P,
Inghirami G,
Astolfi M,
Ladetto M,
Voena C,
Ballerini P,
Gu W,
Nilsson K,
Knowles DM,
Boccadoro M,
Pileri A,
Dalla-Favera R:
Inactivation of tumor suppressor genes, p53 and Rb1, in plasma cell dyscrasias.
Leukemia
8:758,
1994[Medline]
[Order article via Infotrieve]
15.
Owen RG,
Davis SAA,
Randerson J,
Rawstron AC,
Davies F,
Child JA,
Jack AS,
Morgan GJ:
p53 gene mutations in multiple myeloma. J Clin Pathol:
Mol Pathol
50:18,
1997[Abstract/Free Full Text]
16.
Döhner H,
Fischer K,
Bentz M,
Hansen K,
Benner A,
Cabot G,
Diehl D,
Schlenk R,
Coy J,
Stilgenbauer S,
Volkmann M,
Galle PR,
Poustka A,
Hunstein W,
Lichter P:
p53 gene deletion predicts for poor survival and non-response to therapy with purine analogs in chronic B-cell leukemias.
Blood
85:1580,
1995[Abstract/Free Full Text]
17.
Dewald GW,
Kyle RA,
Hicks GA,
Greipp PR:
The clinical significance of cytogenetic studies in 100 patients with multiple myeloma, plasma cell leukemia, or amyloidosis.
Blood
66:380,
1985[Abstract/Free Full Text]
18.
Gould J,
Alexanian R,
Goodacre A,
Pathak S,
Hecht B,
Barlogie B:
Plasma cell karyotype in multiple myeloma.
Blood
71:453,
1988[Abstract/Free Full Text]
19. Weh HJ, Gutensohn K, Selbach J, Kruse R, Wacker-Backhaus G,
Seeger D, Fiedler W, Fett W, Hossfeld DK: Karyotype in multiple myeloma
and plasma cell leukaemia. Eur J Cancer 29A:1269, 1993
20.
Lai JL,
Zandecki M,
Mary JY,
Bernardi F,
Izydorczyk V,
Flactif M,
Morel P,
Jouet JP,
Bauters F,
Facon T:
Improved cytogenetics in multiple myeloma: A study of 151 patients including 117 patients at diagnosis.
Blood
85:2490,
1995[Abstract/Free Full Text]
21.
Sawyer JR,
Waldron JA,
Jagannath S,
Barlogie B:
Cytogenetic findings in 200 patients with multiple myeloma.
Cancer Genet Cytogenet
82:41,
1995[Medline]
[Order article via Infotrieve]
22.
Calasanz MJ,
Cigudosa JC,
Odero MD,
Ferreira C,
Ardanaz MT,
Fraile A,
Carrasco JL,
Sole F,
Cuesta B,
Gullon A:
Cytogenetic analysis of 280 patients with multiple myeloma and related disorders: Primary breakpoints and clinical correlations.
Genes Chromosomes Cancer
18:84,
1997[Medline]
[Order article via Infotrieve]
23.
Drach J,
Schuster J,
Nowotny H,
Angerler J,
Rosenthal F,
Fiegl M,
Rothermundt C,
Gsur A,
Jäger U,
Heinz R,
Lechner K,
Ludwig H,
Huber H:
Multiple myeloma: High incidence of chromosomal aneuploidy as detected by interphase fluorescence in situ hybridization.
Cancer Res
55:3854,
1995[Abstract/Free Full Text]
24.
Flactif M,
Zandecki M,
Lai JL,
Bernardi F,
Obein V,
Bauters F,
Facon T:
Interphase fluorescence in situ hybridization (FISH) as a powerful tool for the detection of aneuploidy in multiple myeloma.
Leukemia
9:2109,
1995[Medline]
[Order article via Infotrieve]
25.
Tabernero D,
San Miguel JF,
Garcia-Sanz R,
Najera L,
Garcia-Isidoro M,
Perez-Simon JA,
Gonzalez M,
Wiegant J,
Raap AK,
Orfao A:
Incidence of numerical chromosome changes in multiple myeloma. Fluorescence in situ hybridization analysis using 15 chromosome-specific probes.
Am J Pathol
149:153,
1996[Abstract]
26.
Zandecki M,
Lai JL,
Facon T:
Multiple myeloma: Almost all patients are cytogenetically abnormal.
Br J Haematol
94:217,
1996[Medline]
[Order article via Infotrieve]
27.
Chronic Leukemia-Myeloma Task Force:
Proposed guidelines for protocol studies: II. Plasma cell myeloma.
Cancer Chemother Rep
4:145,
1973
28.
Fain PR,
Solomon E,
Ledbetter:
Second International Workshop on human chromosome 17.
Cytogenet Cell Genet
57:66,
1991[Medline]
[Order article via Infotrieve]
29.
Drach J,
Angerler J,
Schuster J,
Rothermundt C,
Thalhammer R,
Haas OA,
Jäger U,
Fiegl M,
Geissler K,
Ludwig H,
Huber H:
Interphase fluorescence in situ hybridization identifies chromosomal abnormalities in plasma cells from patients with monoclonal gammopathy of undetermined significance.
Blood
86:3915,
1995[Abstract/Free Full Text]
30.
Schweizer D:
Simultaneous fluorescent staining of R bands and specific heterochromatic regions (DA-DAPI bands) in human chromosomes.
Cytogenet Cell Genet
27:190,
1980[Medline]
[Order article via Infotrieve]
31.
Schweizer D:
Counterstain-enhanced chromosome banding.
Hum Genet
57:1,
1981[Medline]
[Order article via Infotrieve]
32. Mitelman F: ISCN Guidelines for Cancer Cytogenetics. Supplement
to an International System for Human Cytogenetic Nomenclature. Basel,
Switzerland, Karger, 1991
33.
Avet-Loiseau H,
Andree-Ashley LE,
Moore D,
Mellerin MP,
Feusner J,
Bataille R,
Pallavicini MG:
Molecular cytogenetic abnormalities in multiple myeloma and plasma cell leukemia measured using comparative genomic hybridization.
Genes Chromosomes Cancer
19:124,
1997[Medline]
[Order article via Infotrieve]
34.
van den Berghe H:
Chromosomes in plasma-cell malignancies.
Eur J Haematol
45:47,
1990
35.
Okuda T,
Shurtleff SA,
Valentine MB,
Raimondi SC,
Head DR,
Behm F,
Curcio-Brint AM,
Liu Q,
Pui C-H,
Sherr CJ,
Beach D,
Look AT,
Downing JR:
Frequent deletion of p16INK4a/MTS1 and p15INK4b/MTS2 in pediatric acute lymphoblastic leukemia.
Blood
85:2331,
1995[Abstract/Free Full Text]
36.
Leblanc T,
Derre J,
Flexor M,
Le Coniat M,
Leroux D,
Rimokh R,
Larsen C-J,
Berger R:
FISH analysis of translocations involving the short arm of chromosome 9 in lymphoid malignancies.
Genes Chromosomes Cancer
19:273,
1997[Medline]
[Order article via Infotrieve]
37.
Kobayashi H,
Montgomery KT,
Bohlander SK,
Adra CN,
Lim BL,
Kucherlapati RS,
Donis-Keller H,
Holt MS,
Le Beau MM,
Rowley JD:
Fluorescence in situ hybridization mapping of translocations and deletions involving the short arm of human chromosome 12 in malignant hematologic diseases.
Blood
84:3473,
1994[Abstract/Free Full Text]
38.
Kobayashi H,
Rowley JD:
Identification of cytogenetically undetected 12p13 translocations and associated deletions with fluorescence in situ hybridization.
Genes Chromosomes Cancer
12:66,
1995[Medline]
[Order article via Infotrieve]
39.
Höglund M,
Johansson B,
Pedersen-Bjergaard J,
Marynen P,
Mitelman F:
Molecular characterization of 12p abnormalities in hematologic malignancies: Deletion of KIP1, rearrangement of TEL, and amplification of CCND2.
Blood
87:324,
1996[Abstract/Free Full Text]
40.
Wlodarska I,
Marynen P,
La Starza R,
Mecucci C,
van den Berghe H:
The ETV6, CDKN1B and D12S178 loci are involved in a segment commonly deleted in various 12p aberrations in different hematological malignancies.
Cytogenet Cell Genet
72:229,
1996[Medline]
[Order article via Infotrieve]
41.
Andreasson P,
Johansson B,
Arheden K,
Billström R,
Mitelman F,
Höglund M:
Deletions of CDKN1B and ETV6 in acute myeloid leukemia and myelodysplastic syndromes without cytogenetic evidence of 12p abnormalities.
Genes Chromosomes Cancer
19:77,
1997[Medline]
[Order article via Infotrieve]
42.
Momand J,
Zambetti GP,
Olson DC,
George D,
Levine AJ:
The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation.
Cell
69:1237,
1992[Medline]
[Order article via Infotrieve]
43.
Teoh G,
Urashima M,
Ogata A,
Chauhan D,
DeCaprio JA,
Treon SP,
Schlossman RL,
Anderson KC:
MDM2 protein overexpression promotes proliferation and survival of multiple myeloma cells.
Blood
90:1982,
1997[Abstract/Free Full Text]
44.
Lotem J,
Sachs L:
Hematopoietic cells from mice deficient in wild-type p53 are more resistant to induction of apoptosis by some agents.
Blood
82:1092,
1993[Abstract/Free Full Text]
45.
Lane D:
p53, guardian of the genome.
Nature
358:15,
1993
46.
Carson DA,
Lois A:
Cancer progression and p53.
Lancet
346:1009,
1995[Medline]
[Order article via Infotrieve]
47.
Tricot G,
Sawyer J,
Jagannath S,
Bracy D,
Mattox S,
Vesole D,
Naucke S,
Barlogie B:
Poor prognosis in multiple myeloma is associated only with partial or complete deletions of chromosome 13 or abnormalities involving 11q and not with other karyotype abnormalities.
Blood
86:4250,
1995[Abstract/Free Full Text]
48.
Tricot G,
Sawyer JR,
Jagannath S,
Desikan KR,
Siegel R,
Naucke S,
Mattox S,
Bracy D,
Munshi N,
Barlogie B:
Unique role of cytogenetics in the prognosis of patients with myeloma receiving high-dose therapy and autotransplants.
J Clin Oncol
15:2659,
1997[Abstract/Free Full Text]
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
H. Avet-Loiseau, C. Li, F. Magrangeas, W. Gouraud, C. Charbonnel, J.-L. Harousseau, M. Attal, G. Marit, C. Mathiot, T. Facon, et al.
Prognostic Significance of Copy-Number Alterations in Multiple Myeloma
J. Clin. Oncol.,
September 20, 2009;
27(27):
4585 - 4590.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Reece, K. W. Song, T. Fu, B. Roland, H. Chang, D. E. Horsman, A. Mansoor, C. Chen, E. Masih-Khan, Y. Trieu, et al.
Influence of cytogenetics in patients with relapsed or refractory multiple myeloma treated with lenalidomide plus dexamethasone: adverse effect of deletion 17p13
Blood,
July 16, 2009;
114(3):
522 - 525.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. Xiong, X. Wu, S. Starnes, S. K. Johnson, J. Haessler, S. Wang, L. Chen, B. Barlogie, J. D. Shaughnessy Jr, and F. Zhan
An analysis of the clinical and biologic significance of TP53 loss and the identification of potential novel transcriptional targets of TP53 in multiple myeloma
Blood,
November 15, 2008;
112(10):
4235 - 4246.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Bochtler, U. Hegenbart, F. W. Cremer, C. Heiss, A. Benner, D. Hose, M. Moos, J. Bila, C. R. Bartram, A. D. Ho, et al.
Evaluation of the cytogenetic aberration pattern in amyloid light chain amyloidosis as compared with monoclonal gammopathy of undetermined significance reveals common pathways of karyotypic instability
Blood,
May 1, 2008;
111(9):
4700 - 4705.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. C. Munshi
Investigative Tools for Diagnosis and Management
Hematology,
January 1, 2008;
2008(1):
298 - 305.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. W. Jenner, P. E. Leone, B. A. Walker, F. M. Ross, D. C. Johnson, D. Gonzalez, L. Chiecchio, E. Dachs Cabanas, G. Paolo Dagrada, M. Nightingale, et al.
Gene mapping and expression analysis of 16q loss of heterozygosity identifies WWOX and CYLD as being important in determining clinical outcome in multiple myeloma
Blood,
November 1, 2007;
110(9):
3291 - 3300.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Wavre, A. S. Baur, M. Betz, D. Muhlematter, M. Jotterand, K. Zaman, and N. Ketterer
Case study of intracerebral plasmacytoma as an initial presentation of multiple myeloma
Neuro-oncol,
July 1, 2007;
9(3):
370 - 372.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Avet-Loiseau, M. Attal, P. Moreau, C. Charbonnel, F. Garban, C. Hulin, S. Leyvraz, M. Michallet, I. Yakoub-Agha, L. Garderet, et al.
Genetic abnormalities and survival in multiple myeloma: the experience of the Intergroupe Francophone du Myelome
Blood,
April 15, 2007;
109(8):
3489 - 3495.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Fonseca and A. K. Stewart
Targeted therapeutics for multiple myeloma: The arrival of a risk-stratified approach
Mol. Cancer Ther.,
March 1, 2007;
6(3):
802 - 810.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Dispenzieri, S. V. Rajkumar, M. A. Gertz, M. Q. Lacy, R. A. Kyle, P. R. Greipp, T. E. Witzig, J. A. Lust, S. J. Russell, S. R. Hayman, et al.
Treatment of Newly Diagnosed Multiple Myeloma Based on Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART): Consensus Statement
Mayo Clin. Proc.,
March 1, 2007;
82(3):
323 - 341.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. A. Walker, P. E. Leone, M. W. Jenner, C. Li, D. Gonzalez, D. C. Johnson, F. M. Ross, F. E. Davies, and G. J. Morgan
Integration of global SNP-based mapping and expression arrays reveals key regions, mechanisms, and genes important in the pathogenesis of multiple myeloma
Blood,
September 1, 2006;
108(5):
1733 - 1743.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Stuhmer, M. Chatterjee, M. Hildebrandt, P. Herrmann, H. Gollasch, C. Gerecke, S. Theurich, L. Cigliano, R. A. Manz, P. T. Daniel, et al.
Nongenotoxic activation of the p53 pathway as a therapeutic strategy for multiple myeloma
Blood,
November 15, 2005;
106(10):
3609 - 3617.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Z. Chen, B. Issa, S. Huang, E. Aston, J. Xu, M. Yu, A. R. Brothman, and M. Glenn
A Practical Approach to the Detection of Prognostically Significant Genomic Aberrations in Multiple Myeloma
J. Mol. Diagn.,
November 1, 2005;
7(5):
560 - 565.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. K. Stewart and R. Fonseca
Prognostic and Therapeutic Significance of Myeloma Genetics and Gene Expression Profiling
J. Clin. Oncol.,
September 10, 2005;
23(26):
6339 - 6344.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S.-Y. Huang, M. Yao, J.-L. Tang, W. Tsay, F.-Y. Lee, M.-C. Liu, C.-H. Wang, Y.-C. Chen, M.-C. Shen, and H.-F. Tien
Clinical significance of cytogenetics and interphase fluorescence in situ hybridization analysis in newly diagnosed multiple myeloma in Taiwan
Ann. Onc.,
September 1, 2005;
16(9):
1530 - 1538.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Chang, C. Qi, Q.-L. Yi, D. Reece, and A. K. Stewart
p53 gene deletion detected by fluorescence in situ hybridization is an adverse prognostic factor for patients with multiple myeloma following autologous stem cell transplantation
Blood,
January 1, 2005;
105(1):
358 - 360.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Hideshima, P. L. Bergsagel, W. M. Kuehl, and K. C. Anderson
Advances in biology of multiple myeloma: clinical applications
Blood,
August 1, 2004;
104(3):
607 - 618.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Fonseca, B. Barlogie, R. Bataille, C. Bastard, P. L. Bergsagel, M. Chesi, F. E. Davies, J. Drach, P. R. Greipp, I. R. Kirsch, et al.
Genetics and Cytogenetics of Multiple Myeloma: A Workshop Report
Cancer Res.,
February 15, 2004;
64(4):
1546 - 1558.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Fonseca, E. Blood, M. Rue, D. Harrington, M. M. Oken, R. A. Kyle, G. W. Dewald, B. Van Ness, S. A. Van Wier, K. J. Henderson, et al.
Clinical and biologic implications of recurrent genomic aberrations in myeloma
Blood,
June 1, 2003;
101(11):
4569 - 4575.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Barille-Nion, B. Barlogie, R. Bataille, P. L. Bergsagel, J. Epstein, R. G. Fenton, J. Jacobson, W. M. Kuehl, J. Shaughnessy, and G. Tricot
Advances in Biology and Therapy of Multiple Myeloma
Hematology,
January 1, 2003;
2003(1):
248 - 278.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Leroy, C. Haioun, E. Lepage, N. Le Metayer, F. Berger, E. Labouyrie, V. Meignin, B. Petit, C. Bastard, G. Salles, et al.
p53 gene mutations are associated with poor survival in low and low-intermediate risk diffuse large B-cell lymphomas
Ann. Onc.,
July 1, 2002;
13(7):
1108 - 1115.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Puerto, M.J. Ramirez, R. Marcos, A. Creus, and J. Surralles
Radiation-induced chromosome aberrations in human euchromatic (17cen-p53) and heterochromatic (1cen-1q12) regions
Mutagenesis,
July 1, 2001;
16(4):
291 - 296.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. M. Gruszka-Westwood, R. A. Hamoudi, E. Matutes, E. Tuset, and D. Catovsky
p53 abnormalities in splenic lymphoma with villous lymphocytes
Blood,
June 1, 2001;
97(11):
3552 - 3558.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Franke, I. Wlodarska, B. Maes, P. Vandenberghe, J. Delabie, A. Hagemeijer, and C. De Wolf-Peeters
Lymphocyte predominance Hodgkin disease is characterized by recurrent genomic imbalances
Blood,
March 15, 2001;
97(6):
1845 - 1853.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Zojer, R. Konigsberg, J. Ackermann, E. Fritz, S. Dallinger, E. Kromer, H. Kaufmann, L. Riedl, H. Gisslinger, S. Schreiber, et al.
Deletion of 13q14 remains an independent adverse prognostic variable in multiple myeloma despite its frequent detection by interphase fluorescence in situ hybridization
Blood,
March 15, 2000;
95(6):
1925 - 1930.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Konigsberg, N. Zojer, J. Ackermann, E. Kromer, H. Kittler, E. Fritz, H. Kaufmann, T. Nosslinger, L. Riedl, H. Gisslinger, et al.
Predictive Role of Interphase Cytogenetics for Survival of Patients With Multiple Myeloma
J. Clin. Oncol.,
February 14, 2000;
18(4):
804 - 804.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Filipits, J. Drach, G. Pohl, J. Schuster, T. Stranzl, J. Ackermann, R. Konigsberg, H. Kaufmann, H. Gisslinger, H. Huber, et al.
Expression of the Lung Resistance Protein Predicts Poor Outcome in Patients with Multiple Myeloma
Clin. Cancer Res.,
September 1, 1999;
5(9):
2426 - 2430.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
Abstract
Introduction
Abstract
