|
|
 Previous Article | Table of Contents | Next Article 
Blood, Vol. 93 No. 12 (June 15), 1999:
pp. 4365-4374
Increased Number of Chromosomal Imbalances and High-Level DNA
Amplifications in Mantle Cell Lymphoma Are Associated With Blastoid
Variants
By
Sílvia Beà,
Maria Ribas,
Jesús M. Hernández,
Francesc Bosch,
Magda Pinyol,
Luis Hernández,
Juan Luis García,
Teresa Flores,
Marcos González,
Armando López-Guillermo,
Miguel A. Piris,
Antonio Cardesa,
Emilio Montserrat,
Rosa Miró, and
Elías Campo
From the Hematopathology Section, Laboratory of Anatomic Pathology,
and Department of Hematology, Hospital Clínic, Institut
d'Investigacions Biomèdiques "August Pi i Sunyer"
(IDIBAPS), University of Barcelona, Barcelona, Spain; the Department of
Cellular Biology and Physiology, Autonomous University of Barcelona,
Barcelona, Spain; the Laboratory of Anatomic Pathology, Hospital Virgen
de la Salud, Toledo, Spain; and the Department of Hematology, Hospital
Clínico, Universidad de Salamanca, Salamanca, Spain.
 |
ABSTRACT |
Mantle cell lymphomas (MCLs) are characterized by 11q13 chromosomal
translocations and cyclin D1 overexpression. The secondary genetic and
molecular events involved in the progression of these tumors are not
well known. In this study, we have analyzed 45 MCLs (32 typical and 13 blastoid variants) by comparative genomic hybridization (CGH). To
identify the possible genes included in the abnormal chromosome
regions, selected cases were analyzed for P53,
P16INK4a, RB, C-MYC, N-MYC, BCL2, BCL6,
CDK4, and BMI-1 gene alterations. The most frequent
imbalances detected by CGH were gains of chromosomes 3q (49%), 7p
(27%), 8q (22%), 12q (20%), 18q (18%), and 9q34 (16%) and losses
of chromosomes 13 (44%), 6q (27%), 1p (24%), 11q14-q23 (22%),
10p14-p15 (18%), 17p (16%), and 9p (16%). High-level DNA amplifications were identified in 11 different regions of the genome,
predominantly in 3q27-q29 (13%), 18q23 (9%), and Xq28 (7%). The CGH
analysis allowed the identification of regional consensus areas in most
of the frequently involved chromosomes. Chromosome gains
(P = .02) and losses (P = .01) and DNA
amplifications (P = .015) were significantly higher in
blastoid variants. The significant differences between blastoid and
typical tumors were gains of 3q, 7p, and 12q, and losses of 17p. CGH
losses of 17p correlated with P53 gene deletions and mutations.
Similarly, gains of 12q and high-level DNA amplifications of 10p12-p13
were associated with CDK4 and BMI-1 gene
amplifications, respectively. One of 2 cases with 8q24 amplification
showed C-MYC amplification by Southern blot. Alterations in 2p,
3q, 13, and 18q were not associated with N-MYC, BCL6, RB, or
BCL2 alterations, respectively, suggesting that other genes may
be the targets of these genetic abnormalities in MCLs. Increased number
of gains (0 v 1-4 v >4 gains per case) (P = .002), gains of 3q (P = .02), gains of 12q
(P = .03), and losses of 9p (P = .003) were
significantly associated with a shorter survival of the patients. These
results indicate that an increased number of chromosome imbalances are
associated with blastoid variants of MCLs and may have prognostic significance.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
MANTLE CELL LYMPHOMA (MCL) is a malignant
lymphoproliferative disorder derived from naive pregerminal center
CD5+ B cells expressing IgM/D.1
Morphologically, the typical variant of MCL is composed of a monotonous
proliferation of small to medium-sized lymphocytes with irregular
nuclei and relatively low proliferative activity.1 Several
studies have also recognized a blastoid variant in which the cells may
show either rounder nuclei with fine and disperse chromatin resembling
lymphoblasts or larger, deeply indented, and pleomorphic nuclei with
occasional nucleoli.2,3 These blastoid variants have a
higher proliferative activity and a more aggressive biological behavior
than the typical variants of the tumor.2-4
Genetically, MCLs are characterized by chromosomal translocations
involving the 11q13 region and its molecular counterpart bcl-1
rearrangement, which results in the overexpression of cyclin D1
gene.5,6 The identification of this translocation in
virtually all cases of MCL and the constant cyclin D1 overexpression in the tumors indicate that these molecular phenomena are important mechanisms in their pathogenesis.7,8 Experimental studies have shown that cyclin D1 may function as an oncogene in the malignant transformation of different cell types. However, the tumorigenic and
transforming properties of cyclin D1 seem to be less effective than
other oncogenes.9 On the other hand, cyclin D1 transgenic animals do not develop spontaneous lymphomas, and lymphomagenesis in
these animals requires the cooperation with other oncogenes such as
C-MYC.10 All of these findings suggest that other
mechanisms, in addition to cyclin D1 deregulation, may participate in
the development and progression of MCLs.
The secondary genetic and molecular events involved in the pathogenesis
of these tumors are not well known. Recent studies indicate that
blastoid variants of MCLs harbor more frequent bcl-1 rearrangements at
the major translocation cluster locus2 and have a higher
incidence of P53 gene mutations11,12 and
P16INK4a deletions than typical
variants.13,14 Classic cytogenetic studies have identified
additional chromosome abnormalities besides the 11q13 translocations in
some MCLs.15-19 However, these studies are limited, and no
correlations with the morphologic variants or the biological behavior
of the tumor have been described. Chromosomal banding techniques are
useful for the identification of chromosomal aberrations and
imbalances, but they are less reliable for the recognition of
potentially amplified regions. On the other hand, these techniques
require the analysis of metaphases upon cell culture that may induce a
certain subclone selection and underrepresentation of tumor clones. The
relatively new technique of comparative genomic hybridization (CGH)
allows a rapid analysis of chromosomal imbalances within the tumor
genome including mapping of high-level DNA amplifications without the
requirement of cell culturing and metaphase preparation.20
The aims of this study were to determine the secondary chromosomal
imbalances and high-level DNA amplifications that may play a role in
the development and progression of MCLs, to analyze the potential
involvement of specific genes located in the altered chromosomal
regions in the different variants of MCLs, and to determine the
clinical and pathological relevance of these genetic alterations.
| |
MATERIALS AND METHODS |
Case selection.
Tumor specimens from 45 MCLs were included in the study. There were 33 males and 12 females. A total of 29 cases were obtained from the
Hospital Clínic Provincial of Barcelona; 10 cases from the
Hospital Clínico Universitario, Salamanca; and 6 from the Hospital Virgen de la Salud, Toledo, Spain. A total of 32 cases were
classified as typical MCLs and 13 as blastoid variants of MCLs,
according to previously described criteria.1-3 All cases were studied at diagnosis and were reviewed and classified by three of
us (E.C., M.A.P., and T.F.). The immunophenotype of the tumors was
analyzed using immunohistochemistry on tissue sections and/or cell
suspensions by flow cytometry. These studies included Ig light and
heavy chains, several B-cell (CD19, CD20, CD22, CD45RA, and CD79a) and
T-cell (CD2, CD3, CD5, CD7, CD4, CD8, CD45RO, and CD43) markers, CD10,
and CD23. Cyclin D1 expression was examined in all cases by Northern
blot analysis and/or immunohistochemistry.7 Bcl-1
rearrangement was also examined in all cases by Southern blot analysis
or polymerase chain reaction (PCR) according to a previously described
method.21 Cytogenetic analysis could be performed in 7 cases. All tumors included in the study had a B-cell phenotype and all,
except one blastoid case, coexpressed CD5. The only CD5
tumor had a bcl-1 rearrangement at the MTC locus detected by Southern
blot and PCR, and cyclin D1 overexpression by Northern blot and
immunohistochemistry. Cyclin D1 overexpression was observed in all
tumors. Bcl-1 rearrangement was detected in 20 (44%) tumors. In
addition, 4 of the 7 cases examined by cytogenetic analysis had the
t(11;14)(q13;q32) translocation.
DNA extraction.
High molecular weight DNA was extracted from 42 lymph nodes and 3 involved peripheral blood with the use of the standard Proteinase K/RNAse treatment and phenol-chloroform extraction. Normal DNA was
obtained from 4 male and 1 female healthy blood donors. DNA was diluted
to a concentration of 40 to 60 ng/µL, and 1 µL of each sample was
analyzed in a 0.8% agarose gel and stained with ethidium bromide to
verify its quality and concentration.
CGH.
Normal and tumor DNA were labeled with Spectrum Red-dUTP and Spectrum
Green-dUTP by nick translation using a commercial kit (Vysis, Downers
Grove, IL). Subsequently, equal amounts of normal and tumor labeled
probes (500 ng) and 10 µg of Cot-1 DNA were coprecipitated with the
use of ethanol. The precipitated DNA was dissolved in 12 µL of
hybridization buffer and denatured at 74°C for 8 minutes. Normal
metaphase spreads (Vysis) were denatured for 5 minutes at 74°C and
hybridized with the DNA mixture in a moist chamber for 2 to 3 days.
Slides were washed according to the protocol supplied by the
manufacturer. Chromosomes were counterstained with
4,6-diamino-2-phenylindole (DAPI), resulting in a G banding-like pattern that was used for chromosome identification.
Slides were analyzed with the use of Cytovision Ultra workstation
(Applied Imaging, Sunderland, UK). The fluorescent hybridization signals and DAPI-staining patterns were captured. The software performed a calculation of the tumor DNA to normal DNA fluorescent ratios along the length of each chromosome. Ratio values obtained from
at least 10 metaphase spreads were averaged, and the resulting profiles
were plotted next to the chromosomal ideograms. Ratio values greater
than 1.25 and less than 0.75 were considered to represent chromosomal
gains and losses, respectively. A high-level DNA amplification was
considered when the fluorescence ratio values exceeded 1.5, and, in
addition, a distinct band-like hybridization signal of the tumor DNA
was seen. Negative control experiments were performed using
differentially labeled male versus male DNA and female versus female
DNA. In addition, control experiments in which the Red-dUTP and
Green-dUTP labels were interchanged between normal and tumor were also performed.
Southern blot analysis.
Genomic DNA (15 µg) was digested with EcoRI, HindIII,
and/or BamHI restriction enzymes (BRL, Gaithersburg, MD),
separated on 0.8% agarose gels, and transferred to Hybond-N membranes
(Amersham, Buckinghamshire, UK). The membranes were prehybridized;
hybridized with the P53, P16INK4a,
BCL6, BCL2, C-MYC, N-MYC, RB, CDK4, BMI-1, and
 -ACTIN probes; and washed as previously
described.7
Probes.
The P53 probe was a 2.0-kb EcoRI-BamHI fragment
of the p1A65 (pArgSP53) cDNA clone containing the entire coding region
of the human P53 gene, which was kindly provided by Dr L.V.
Crawford (Imperial Cancer Research Foundation, Cambridge,
UK).22 The P16INK4a probe was a
fragment of exon 2 obtained by PCR with the use of primers previously
described.13 The BCL6 probe was a 1.4-kb EcoRI-Bgl II fragment of the partial cDNA clone of
BCL6 gene, which was kindly provided by Dr B.W. Baron
(University of Chicago, Chicago, IL).23 The BCL2
probe was a 1.5-kb HindIII fragment of the partial cDNA clone
of BCL2 gene, which was kindly provided by Dr J. Boix
(University of Lleida, Lleida, Spain).24 The
C-MYC probe was a 1.4-kb Cla I-EcoRI fragment
containing the third coding exon, which was kindly provided by Dr R. Dalla Favera (Columbia University, New York, NY). The N-MYC
probe was a 1.0-kb EcoRI-BamHI coding fragment of exon
2 (Oncor, Gaithersburg, MD). The RB probes were Rb0.9 and Rb3.8
representing the 5' and 3' portions of RB cDNA, which was
kindly provided by Dr R.A. Weinberg (Whitehead Institute, Cambridge,
MA).25 The CDK4 probe was a 1.2-kb
BamHI/Sma I full cDNA, which was kindly provided by Dr
M. Serrano (Centro Nacional Biotecnologia, Madrid,
Spain).26 The BMI-1 probe was a 1.5-kb Pst
I fragment of the partial cDNA, which was kindly provided by Dr M. van
Lohuizen (The Netherlands Cancer Institute, Amsterdam, The
Netherlands).27 Probes were radiolabeled using a random
primer DNA labeling kit (Amersham) with [ -32P]-dCTP.
To normalize the DNA loading, the blots were hybridized with a
-ACTIN probe. The signals were quantified using
a Fuji Photo Film system (Image Gauge version 2.5.3, Tokyo, Japan).
Statistical analysis.
Differences among the histologic variants and other initial and
evolutive characteristics of the patients in terms of the CGH
imbalances were compared by the Fisher's exact test (two-tailed). The
differences observed between means of gains, losses or amplifications, and the histologic subtype were compared using the Student's
t-test when the data fulfill the criteria for parametric
statistics. Nonparametric tests were used when necessary
(U-Mann-Whitney). The actuarial survival analysis was performed
according to the method described by Kaplan and Meier,28
and the curves were compared by the log rank test.29
| |
RESULTS |
CGH.
Forty of the 45 patients (89%) showed gains (total, 124) or losses
(total, 109) of genetic material (Figs 1 and
2). All of the
altered cases, except for 5, showed more than one chromosome imbalance.
The single alterations identified in these cases were trisomy X (case
35), trisomy 3 (case 17), monosomy 14 (case 41), gain of 18q23 (case
31), and trisomy 20 (case 8). Irrespective of the morphology of the
lymphoma, the most frequent imbalances were gains of chromosomes 3q
(49%), 7p (27%), 8q (22%), 12q (20%), 18q (18%), and 9q34 (16%)
(Table 1). High-level DNA amplifications were identified in 11 different regions of the genome, predominantly in
3q27-q29 (13%), 18q23 (9%), and Xq28 (7%) (Table
2). Eight of the 11 (73%) amplifications
were localized in chromosomal regions in which known fragile sites have
been identified (3q27-q29 and FRA3C, Xq28 and FRAXF, 8q24 and FRA8C,
2p25 and FRA2C, 7p22 and FRA7B, 13q31-q32 and FRA13D, 3q24-q25 and
FRA3D, and 17q23-q25 and FRA17B). The most frequent losses were on
chromosome 13 (44%), 6q (27%), 1p (24%), 11q14-q23 (22%), 10p14-p15
(18%), 17p (16%), and 9p (16%) (Table
3).
View larger version (35K):
[in this window]
[in a new window]
| Fig 1.
Summary of the CGH data in 32 cases of typical MCL. Lines
on the left side of the ideogram indicate loss of chromosomal material;
lines on the right side indicate gain of chromosomal material. Thick
black bars represent chromosomal gains exceeding 1.5 in a large
chromosomal region. High-level DNA amplifications are represented as
solid squares. Each line represents a gained or lost region in a single
tumor.
|
|
View larger version (35K):
[in this window]
[in a new window]
| Fig 2.
Summary of the CGH data in 13 cases of blastoid MCL.
Lines on the left side of the ideogram indicate loss of chromosomal
material; lines on the right side indicate gain of chromosomal
material. Thick black bars represent chromosomal gains exceeding 1.5 in
a large chromosomal region. High-level DNA amplifications are
represented as solid squares. Each line represents a gained or lost
region in a single tumor.
|
|
Chromosome imbalances were significantly more frequent in blastoid
variants (mean of 10.1 ± 4.89 per case) than in typical tumors
(mean of 3.87 ± 3.08 per case; P = .0001). The summary of
chromosomal imbalances detected in these patients is shown in Figs 1
and 2 and in Tables 1 through 3. Blastoid MCLs had a total of 65 chromosome gains (mean, 5.0 ± 3.27) and 16 high-level DNA
amplifications (mean, 1.23 ± 1.25), whereas only 59 gains (mean,
1.84 ± 1.68) and 8 amplifications (mean, 0.25 ± 0.52) were identified in typical cases (P = .02 and P = .015,
respectively). Similarly, chromosome losses were also significantly
higher in blastoid (mean, 4.3 ± 2.42) than in typical tumors (mean,
1.65 ± 1.77; P = .01). Most chromosome imbalances were
similarly distributed in typical and blastoid tumors. However, a number
of particular alterations were more frequent in blastoid MCLs. The
significant differences between the two variants were gains of 3q, 7p,
and 12q and losses of 17p (Tables 1 through 3).
Considering both typical and blastoid MCLs, CGH analysis allowed the
delimitation of minimal common regions overrepresented or
underrepresented on each of the chromosomes most frequently involved
(Figs 1 and 2 and Tables 1 through 3). Twenty-two cases showed gains of
3q, and two consensus regions could be delimited in 3q27-q29 and 3q25
(case 30). The commonly overrepresented region on chromosome 7 was
mapped to bands 7p15-p22, with a high-level amplification at 7p22 (case
4). On chromosome 8, 2 cases (cases 4 and 24) with high-level
amplifications defined a consensus region in 8q24. For chromosomes 9 and 10, a consensus area of overlap in 9q34 and 10p12-p13,
respectively, could be identified. On chromosome 11 and 12, the
consensus area was delineated to 11q25 and 12q13, respectively. An
amplification (case 6) and two gains (cases 21 and 22) defined the
consensus region 13q22-q32. Interestingly, this region was retained in
2 cases (case 3 and 15) with extensive losses of 13q arm (Figs 1 and
2). On chromosome 18 and X, the consensus region was 18q23 and Xq28,
respectively, with 3 blastoid tumors showing a high-level amplification
at Xq28.
The regions frequently involved by loss of genetic material were
delineated to 1p21-p22 (cases 11 and 28), 10p14-p15 (cases 2, 5, and
16), 11q21-q22 (cases 14 and 16), and 17p13 (cases 5, 25, and 38). On
chromosome 6q, two different areas commonly lost were identified in
6q21-q22 (case 20) and 6q25-q27 (case 12). On chromosome 13, two
different areas were also identified: 13q13-q14 (cases 9 and 21) and
13q33-q34 (cases 37 and 38).
Comparison of CGH results with Southern blot analysis.
To identify the possible genes included in abnormal chromosome regions,
selected cases were analyzed for P53,
P16INK4a, C-MYC, N-MYC, BCL6,
BCL2, RB, CDK4, and BMI-1 gene alterations. The results are
summarized in Tables 4 and
5. The status
of the P53 gene was studied by Southern blot and
single-stranded conformational polymorphism (SSCP)
analysis in the 6 blastoid MCLs with 17p losses. Tumors with an
anomalous SSCP pattern were sequenced. Two of these cases showed
homozygous deletions of the gene (cases 5 and 15; Table 4 and Fig
3A), and the other 4 tumors (cases 1, 2, 3, and 38) had point mutations associated with loss of the remaining
allele. Sixteen additional cases with normal chromosome 17 profile were
also examined molecularly, and no P53 alterations were observed
in any of them. Southern blot analysis confirmed a homozygous deletion
of P16INK4a gene in a case with loss of 9p
by CGH (case 12). Two cases (cases 2 and 5) with a 25% reduction in
the CGH profile of chromosome 9p showed around 20% reduction of the
P16INK4a signal by Southern blot. However,
CGH did not detect loss of 9p in 2 tumors (cases 4 and 6) in which
homozygous deletions of P16INK4a gene were
detected by Southern blot. Fifteen additional cases with normal
chromosome 9 profile were also examined and no
P16INK4a gene alterations were observed
(Table 5).
View this table:
[in this window]
[in a new window]
|
Table 5.
Correlation Between CGH Gains and High-Level DNA
Amplifications and Gene Amplifications by Southern Blot
|
|
View larger version (42K):
[in this window]
[in a new window]
| Fig 3.
Partial CGH karyotypes, corresponding ratio profiles, and
Southern blot analysis of different MCLs. Hybridized tumor DNA was
labeled with Spectrum Red-dUTP and control DNA with Spectrum
Green-dUTP. On the right side of the ideograms, the average ratios of
tumor/normal fluorescence are plotted. The central line indicates a
ratio value of 1.0; lines on the left side indicate ratio values of
0.75 and 0.5, respectively; lines on the right side indicate ratio
values of 1.25 and 1.5, respectively. n = number of chromosomes
analyzed for calculating the respective average ratio profile.
-ACTIN probe was used as loading control in all
Southern blots. (A) (Left) Partial CGH karyotype of case 5. A reduction
of 17p arm is visible. (Right) Southern blot analysis of DNA of the
same case (case 5), another case with a similar chromosome 17 profile
(case 15), an additional case with normal chromosome 17 profile (case
20), and DNA from lymphocytes of a healthy control. Both cases with 17p
loss by CGH (cases 5 and 15) showed homozygous deletions of P53
gene. (B) (Left) Partial CGH karyotype of case 5. A gain of 12q13 is
visible. (Right) Southern blot analysis of DNA of the same case (case
5), another case with gain of 12q by CGH (case 2), an additional tumor
with normal chromosome 12 profile (case 10), and DNA from lymphocytes
of a healthy control. Densitometric evaluation showed an amplification
of CDK4 gene in case 5. (C) (Left) Partial CGH karyotype of
case 1. An intense, band-like hybridization signal mapping to
chromosomal band 10p12-p13 is observed. (Right) Southern blot analysis
of DNA of the same case (case 1), another tumor with a similar profile
of chromosome 10 (case 16), two additional tumors with normal
chromosome 10 profile (cases 20 and 25), and DNA from lymphocytes of a
healthy control. Densitometric evaluation showed an amplification of
BMI-1 gene. (D) (Left) Partial CGH karyotype of case 4. An
intense, band-like hybridization signal mapping to chromosomal band
8q24 is observed. (Right) Southern blot analysis of DNA of the same
case (case 4), two additional tumors with normal chromosome 8 profile
(cases 9 and 3), and DNA from lymphocytes of a healthy control.
Densitometric evaluation showed an amplification of C-MYC gene.
|
|
Five of the 6 MCL with CGH gains of 12q showed a twofold to eightfold
amplification of CDK4 gene, whereas it was in germline configuration in
12 MCL with a normal chromosome 12 CGH profile (Table 5 and Fig 3B).
Similarly, Southern blot analysis confirmed a threefold amplification
of BMI-1 gene in the two tumors with a high-level DNA
amplification of 10p12-p13 (cases 1 and 16), whereas it was in germline
configuration in 7 other tumors with normal chromosome 10 CGH profile
(Table 5 and Fig 3C). A threefold amplification of the C-MYC
gene was detected by Southern blot in one case (case 4), with a
high-level DNA amplification at 8qter by CGH (Table 5 and Fig 3D).
However, no C-MYC alterations were observed in the other case
with 8qter amplification (case 24) or in 4 cases with 8qter gains and
28 cases with normal profiles of chromosome 8.
BCL6 gene was analyzed by Southern blot in 30 MCLs, 19 cases
with gains or high-level DNA amplifications involving 3q27, and 11 cases with a normal profile of chromosome 3 in the CGH analysis. No
amplifications or rearrangements of BCL6 gene were found in any
case. The known HindIII polymorphism was detected in 9% of the
tumors, a frequency similar to that described in normal population (13%).30 No N-MYC alterations were found in 3 tumors with 2pter amplification or gains (cases 2, 5, and 7) or in 9 cases with normal chromosome 2. Similarly, BCL2 gene was found
in germline configuration in 4 cases with a 18qter high-level DNA
amplification, 4 cases with 18q gains, and 10 tumors with a normal
profile of chromosome 8. The status of RB gene had been
previously examined by Southern blot and immunohistochemistry in 11 and
14 tumors, respectively.31 No alteration of the gene was
observed in the Southern blot analysis of 3 cases with loss of
chromosome 13 or in 8 tumors with normal chromosome 13. Similar levels
of RB protein expression were observed both in 6 cases with loss of
chromosome 13 and in 8 tumors with normal chromosome 13 profile.
Clinical significance of CGH imbalances.
The clinical characteristics of the current series of MCLs were similar
to those previously reported4: median age of 62 years
(range, 32 to 81 years), male predominance (male/female ratio, 2.7:1),
frequent palpable spleen (53%), advanced stage (stage IV, 90%), and
extranodal involvement (94%), including bone marrow infiltration in
the majority of cases (87%) and high serum LDH levels in 47%.
Patients with losses of 9p showed high serum LDH more frequently than
the reminders (86% v 36%, respectively; P = .03).
No other correlation was found between the clinical and analytical
parameters at diagnosis and the above-mentioned genetic alterations.
After different treatment approaches (polychemotherapy, 34 cases;
monotherapy with alkylating agents, 5 cases; other, 3 cases), the
complete response (CR) rate was 17%. No significant differences were
found in the CR rate according to the presence of the genetic lesions.
Clinical follow-up was available in 42 patients. The overall survival
(OS) was 3.5 years. Median OS for patients with typical histology was
4.8 years, whereas it was 1.6 years for those with blastoid variants
(P = .005). A number of CGH alterations were associated with
a poorer prognosis. The presence of chromosome gains (0 v 1-4 v >4 gains per case) was related to a poor overall survival
(4-year OS: 68%, 58%, and 0%, respectively; P = 0.02; Fig
4A). When the analysis was restricted to
the 29 patients with typical variants, the presence of chromosome gains
(0 gains v 1-4 gains per case v >4 gains
per case) still retained prognostic significance (P = .03).
Moreover, gains of 3q (patients with normal 3q v patients with
gains of 3q; 4-year OS: 63% v 34%; P = .02), gains
of 12q (normal 12q v gains of 12q; 4-year OS: 55% v
18%; P = .03), and losses of 9p (normal 9p v loss of
9p; 4-year OS: 61% v 0%; P = .003) (Fig 4B) were
associated with a significant shorter survival.
View larger version (35K):
[in this window]
[in a new window]
| Fig 4.
(A) (Left) Survival curves of patients with MCL according
to increased number of gains (0 v 1-4 v >4 gains per case;
P = .02). (B) (Right) Survival curves of patients with MCL
according to losses of 9p (normal 9p v loss of 9p;
P = .003).
|
|
| |
DISCUSSION |
In the present study, we have identified a high number of chromosomal
imbalances and DNA amplifications in MCLs. The most recurrent
alterations observed in our series were gains of 3q, 7p, 8q, 12q, 18q,
and 9q34 and losses of chromosome 13, 6q, 1p, 11q14-q23, 10p14-p15,
17p, and 9p, as well as amplification in 11 different sites. Previous
cytogenetic studies had identified different secondary alterations in
MCLs, including gains and trisomies of chromosomes 3, 7, 12, and 18;
losses of 6q, 1p, 11q, and 13q12-q14; and monosomies 9, 13, and
17.15-19 Our study confirms these chromosomes as recurrent
targets in MCLs, but the frequency of the alterations is higher in the
CGH analysis than in conventional cytogenetic studies. In addition, we
have observed certain imbalances, such as gains of 3q and 8q and losses
of 9p, not previously recognized by classic cytogenetics. A recent CGH
study on MCLs showed similar chromosomal alterations in these tumors,
although the number of high-level DNA amplifications was
lower.32
Most of the individual CGH alterations detected in MCLs have already
been observed in other non-Hodgkin's lymphomas (NHLs). However, the global profile and frequency of these imbalances seem to
be relatively characteristic of MCLs. Trisomy 3 and 3q gains have been
recently found by CGH in 52% of marginal zone lymphomas. However,
alterations in 1p, 7p, 11q, 12q, and 13 were absent or very rare in
these tumors.33 Gains of chromosome 12 have been detected
in primary mediastinal B-cell lymphomas (31%), primary
gastrointestinal large-cell lymphomas (23%), and chronic lymphocytic
leukemias (CLL; 16%). However, other genetic alterations in these tumors, such as gains of 9p (50%) and Xq (31%) in
mediastinal lymphomas and gains of 11q (25%) in gastrointestinal
lymphomas, were different from the abnormalities found in
MCLs.34-38 In addition, CLL and gastrointestinal tumors
showed preferentially trisomy 12 and the most represented band in
mediastinal lymphomas was 12q24, whereas in MCLs the consensus region
was localized at 12q13. Similarly, the global CGH alterations in
follicular lymphomas,39,40 nodal and extranodal large-cell
lymphomas,41-43 and multiple myeloma44 differ
from the pattern observed in MCLs.
Imbalances in the long arm of chromosome 13 were particularly frequent
in MCLs. Deletions in 13q13-q14 are one of the most frequent structural
alterations in CLL.45 Molecular studies have suggested the
existence of a novel tumor-suppressor gene in this region, distal to
RB gene, probably involved in the pathogenesis of
CLL.46 Interestingly, Stilgenbauer et al47 have
recently identified that the chromosomal region 13q14, commonly lost in CLL, is also deleted in 70% of MCLs. Our CGH study, delineating a
consensus region in 13q13-q14 that is frequently lost in MCLs, is
consistent with these molecular findings and supports the idea that
deletions of this region may be important in the development of MCL as
well as in CLL. Other frequent alterations of the long arm of
chromosome 13 were found in our study, particularly deletions of
13q33-q34 and gains of 13q22-q32. The potential target genes in these
regions are not known.
Cytogenetic alterations associated with gene amplification such as
double minute chromosomes and homogeneously staining regions are
relatively rare in NHLs.48 However, CGH studies are
detecting an increased number of high-level DNA amplifications in these tumors, suggesting that gene amplification may be more frequent than
initially thought.49 In this sense, we found 24 high-level DNA amplifications in 16 MCLs involving 11 different regions. Most of
these amplifications have been observed in other NHLs by CGH. However,
amplifications in 7p22 and 17q23-q25 have not been previously
described. The amplifications at Xq28, 13q31-q32, and 10p12-p13 have
only been detected in three MCLs32,49 and a large cell
lymphoma.43
Interestingly, we observed a close relationship between high-level DNA
amplifications and the location of chromosome fragile sites. In fact, 8 of the 11 amplified regions were localized in chromosomal regions where
known fragile sites have been identified. This association between
amplified regions and fragile sites has not been recognized in previous
CGH studies in NHLs. In a recent review of the
literature,50 it can be observed that high-level DNA
amplifications in lymphomas have been found in 27 different chromosomal
regions. Comparing these amplification sites with the location of
fragile sites, 19 (70%) of the amplified regions were indeed
associated with known fragile sites, suggesting that this relationship
may be a general phenomenon. In vitro studies have recently shown that
activation of fragile sites play an important role in the amplification
of chromosomal units by initiating breakage-fusion-bridge cycles and
determining the size of the amplified region. The amplicons at 11q13
and 12q13-q14, which include known human oncogenes, are also associated
with fragile sites.51 Similarly, our findings in this CGH
study and the review of the CGH literature in NHLs expand these
observations and support the hypothesis that fragile sites may be
implicated in the amplification of certain chromosomal regions during
tumor progression.
Molecular studies were performed to correlate the CGH analysis with the
potential alterations of different genes. 17p losses were strongly
associated with P53 gene alterations in our series. Inactivation of P53 gene by mutations and hemizygous deletions is a well-known mechanism in blastoid MCLs and other NHLs and is
associated with 17p abnormalities.11,52 However,
P53 homozygous deletions, as in the 2 cases observed in this
study, are extremely rare in NHLs, although they have been described in
solid tumors.52,53 9p losses were associated with
P16INK4a homozygous deletion in 1 case and
20% reduction in the Southern signal in 2 additional cases. These
findings are consistent with the previous findings of
P16INK4a deletions in MCLs that may be
either homozygous or hemizygous and may only be present in a
subpopulation of tumor cells.13,14
The other genes analyzed in this study have not been previously
examined in MCLs. Interestingly, we have observed CDK4 gene amplification in tumors with 12q gains. CDK4 has been mapped to 12q13, a chromosomal region frequently amplified in different tumors,
particularly gliomas and sarcomas.50,54,55 This chromosomal band also contains GLI and MDM2 genes that may also be
coamplified with CDK4. Amplification of these genes has been
recently observed in diffuse large B-cell lymphomas,56 and
they were associated with advanced stage disease. Our results in MCLs
suggest that CDK4 amplification may also be involved in the
pathogenesis of these tumors. BMI-1 is an oncogene that
participates in murine lymphomagenesis, probably cooperating with
c-myc.27,57 BMI-1 mRNA expression has been detected
in a human Burkitt's lymphoma cell line. BMI-1 has been mapped
to 10p13, a chromosomal region that was found to be amplified in 2 blastoid MCL in our study. Southern blot analysis of these cases showed
that BMI-1 was amplified in these cases, but it was in germline
configuration in other 7 tumors with normal chromosome 10p profile.
These findings suggest that BMI-1 may be a target of this
amplification and it may also play a role in these tumors.
Transgenic animal models have indicated that C-MYC activation
cooperates with cyclin D1 in lymphomagenesis.10 However,
the role of C-MYC in human MCLs is not known. In this study, we
have detected a C-MYC amplification in 1 case with a high-level
DNA amplification at 8qter, but it was in germline configuration in other 10 tumors, including 4 cases with gains of 8qter. No alterations of N-MYC, BCL6, RB, and BCL2 genes were detected in
different number of tumors, including cases with chromosomal
alterations in 2p, 3q, 13q, and 18q, suggesting that these genes do not
play a relevant role in the pathogenesis of MCLs and that other genes may be the targets of these genetic abnormalities in these lymphomas.
Blastoid MCLs have a more aggressive behavior than typical
variants.4 We have now demonstrated that blastoid MCLs have a higher number of chromosomal imbalances and amplifications than typical variants. In addition, specific alterations, including gains of
3q, 7p, and 12q and losses of 17p, were significantly more frequent in
blastoid tumors, suggesting that these alterations could be important
events in the progression of MCLs. Monni et al32 had also
observed a higher number of changes in blastoid variants. However, no
significant differences could be detected between blastoid and typical
cases, probably because of the small number of cases included in their
study.32 The association between 17p and 9p losses and
blastoid MCLs is concordant with previous molecular findings of
P53 and P16INK4a gene alterations
in aggressive MCLs and other NHLs.11-14,58,59 Deletions in 6q and gains of chromosome 7 and 12 have been associated with aggressive histologies in NHLs.16,43,60 Interestingly, gains of 11q and 12q have also been recently associated with aggressive behavior in gastrointestinal large-cell lymphomas.34 These
findings support the idea that, in contrast with the association
between primary genetic alterations and specific lymphomas, certain
secondary genetic events involved in aggressive variants may be similar in different types of lymphomas.16
In this study, we have also examined the clinical significance of CGH
alterations in MCLs. In agreement with other cytogenetic studies in
NHLs,34,60 the complexity of the genetic alterations, and
particularly the number of gains, were significantly associated with a
shortened median survival. Interestingly, the prognostic significance
of the chromosome gains was also found when the analysis was restricted
to the patients with typical variants. Furthermore, gains of 3q and 12q
and losses of 9p were associated with poor prognosis. Structural and
numerical alterations on chromosome 3q have been associated with more
aggressive subtypes of NHLs.61,62 Although BCL6 is
located in 3q27, our results indicate that this gene does not seem to
play an important role in MCLs. The prognostic significance of 9p
losses is concordant with the association between P16INK4a deletion and a worse prognosis in
NHLs.63
In conclusion, we have demonstrated that MCLs have a high number of
chromosomal alterations and DNA amplifications. The pattern of
chromosomal aberrations in these tumors seems to be relatively different from the profile detected in other lymphomas. High-level DNA
amplifications were closely associated with fragile sites, which
support the idea that these structures may participate in chromosomal
amplifications. The significant differences in some alterations between
blastoid and typical variants suggest that they may be involved in the
pathogenesis of these aggressive variants. In addition, our findings
indicate that certain imbalances detected by CGH may be of prognostic
significance in MCLs.
| |
ACKNOWLEDGMENT |
The authors thank Iracema Nayach and Nerea Peiró for their
excellent technical assistance and Eva Cid for her linguistic advice.
| |
FOOTNOTES |
Submitted June 29, 1998; accepted February 9, 1999.
Supported by Grant No. SAF 99/20 from CICYT, Grant No. SAF 96/177,
Maratón-TV3 Cáncer, Asociación Española contra
el Cáncer, and Generalitat de Catalunya SGR52/96. S.B., M.P., and
L.H. were fellows supported by Spanish Ministerio de Educación y
Cultura (S.B.), Maratón-TV3 Cáncer (M.P.), and
Fundació Rius i Virgili (L.H.).
S.B. and M.R. contributed equally to this study.
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 Elías Campo, MD,
Laboratory of Pathology, Hospital Clínic, Villarroel 170, 08036-Barcelona, Spain; e-mail: campo{at}medicina.ub.es.
| |
REFERENCES |
1.
Banks PM, Chan J, Cleary ML, Delsol G, De Wolf-Peeters C, Gatter K, Grogan TM, Harris NL, Isaacson PG, Jaffe ES, Mason D, Pileri S, Ralfkiaer E, Stein H, Warnke R:
Mantle cell lymphoma: A proposal for unification of morphologic, immunologic, and molecular data.
Am J Surg Pathol
16:637, 1992[Medline]
[Order article via Infotrieve]
2.
Ott G, Kalla J, Ott MM, Schryen B, Katzenberger T, Muller JG, Muller-Hermelink HK:
Blastoid variants of mantle cell lymphoma: Frequent bcl-1 rearrangements at the major translocation cluster region and tetraploid chromosome clones.
Blood
89:1421, 1997[Abstract/Free Full Text]
3.
Lardelli P, Bookman MA, Sundeen J, Longo DL, Jaffe ES:
Lymphocytic lymphoma of intermediate differentiation: Morphologic and immunophenotypic spectrum and clinical correlations.
Am J Surg Pathol
14:752, 1990[Medline]
[Order article via Infotrieve]
4.
Bosch F, Lopez Guillermo A, Campo E, Ribera JM, Conde E, Piris MA, Vallespi T, Woessner S, Montserrat E:
Mantle cell lymphoma: Presenting features, response to therapy, and prognostic factors.
Cancer
82:567, 1998[Medline]
[Order article via Infotrieve]
5.
Raffeld M, Jaffe ES:
bcl-1, t(11;14), and mantle cell-derived lymphomas.
Blood
78:259, 1991[Free Full Text]
6.
Rosenberg CL, Wong E, Petty EM, Bale AE, Tsujimoto Y, Harris NL, Arnold A:
PRAD1, a candidate BCL1 oncogene: Mapping and expression in centrocytic lymphoma.
Proc Natl Acad Sci USA
88:9638, 1991[Abstract/Free Full Text]
7.
Bosch F, Jares P, Campo E, Lopez-Guillermo A, Piris MA, Villamor N, Tassies D, Jaffe ES, Montserrat E, Rozman C, Cardesa A:
Prad-1/cyclin D1 gene overexpression in chronic lymphoproliferative disorders: A highly specific marker of mantle cell lymphoma.
Blood
84:2726, 1994[Abstract/Free Full Text]
8.
Vaandrager JW, Schuuring E, Zwikstra E, de Boer CJ, Kleiverda KK, van Krieken JH, Kluin-Nelemans HC, van Ommen GJ, Raap AK, Kluin PM:
Direct visualization of dispersed 11q13 chromosomal translocations in mantle cell lymphoma by multicolor DNA fiber fluorescence in situ hybridization.
Blood
88:1177, 1996[Abstract/Free Full Text]
9.
Hinds PW, Dowdy SF, Eaton EN, Arnold A, Weinberg RA:
Function of a human cyclin gene as an oncogene.
Proc Natl Acad Sci USA
91:709, 1994[Abstract/Free Full Text]
10.
Lovec H, Grzeschiczek A, Kowalski MB, Moroy T:
Cyclin D1/bcl-1 cooperates with myc genes in the generation of B-cell lymphoma in transgenic mice.
EMBO J
13:3487, 1994[Medline]
[Order article via Infotrieve]
11.
Hernandez L, Fest T, Cazorla M, Teruya-Feldstein J, Bosch F, Peinado MA, Piris MA, Montserrat E, Cardesa A, Jaffe ES, Campo E, Raffold M:
P53 gene mutations and protein overexpression are associated with aggressive variants of mantle cell lymphomas.
Blood
87:3351, 1996[Abstract/Free Full Text]
12.
Greiner TC, Moynihan MJ, Chan WC, Lytle DM, Pedersen A, Anderson JR, Weisenburger DD:
P53 mutations in mantle cell lymphoma are associated with variant cytology and predict a poor prognosis.
Blood
87:4302, 1996[Abstract/Free Full Text]
13.
Pinyol M, Hernandez L, Cazorla M, Balbin M, Jares P, Fernandez PL, Montserrat E, Cardesa A, Lopez-Otin C, Campo E:
Deletions and loss of expression of p16ink4a and p21waf1 genes are associated with aggressive variants of mantle cell lymphomas.
Blood
89:272, 1997[Abstract/Free Full Text]
14.
Dreyling MH, Bullinger L, Ott G, Stilgenbauer S, Muller-Hermelink HK, Bentz M, Hiddemann W, Dohner H:
Alterations of the cyclin D1/p16-pRb pathway in mantle cell lymphoma.
Cancer Res
57:4608, 1997[Abstract/Free Full Text]
15.
Weisenburger DD, Sanger WG, Armitage JO, Purtilo DT:
Intermediate lymphocytic lymphoma: Immunophenotypic and cytogenetic findings.
Blood
69:1617, 1987[Abstract/Free Full Text]
16.
Johansson B, Mertens F, Mitelman F:
Cytogenetic evolution patterns in non-Hodgkin's lymphoma.
Blood
86:3905, 1995[Abstract/Free Full Text]
17.
Argatoff LH, Connors JM, Klasa RJ, Horsman DE, Gascoyne RD:
Mantle cell lymphoma: A clinicopathologic study of 80 cases.
Blood
89:2067, 1997[Abstract/Free Full Text]
18.
Nowotny H, Karlic H, Gruner H, Hirsch J, Vesely M, Nader A, Heinz R:
Cytogenetic findings in 175 patients indicate that items of the kiel classification should not be disregarded in the real classification of lymphoid neoplasms.
Ann Hematol
72:291, 1996[Medline]
[Order article via Infotrieve]
19.
Brito-Babapulle V, Ellis J, Matutes E, Oscier D, Khokhar T, MacLennan K, Catovsky D:
Translocation t(11;14)(q13;q32) in chronic lymphoid disorders.
Genes Chromosomes Cancer
5:158, 1992[Medline]
[Order article via Infotrieve]
20.
Houldsworth J, Chaganti RS:
Comparative genomic hybridization: An overview.
Am J Pathol
145:1253, 1994[Abstract]
21.
Pinyol M, Campo E, Nadal A, Terol MJ, Jares P, Nayach I, Fernandez PL, Piris MA, Montserrat E, Cardesa A:
Detection of the bcl-1 rearrangement at the major translocation cluster in frozen and paraffin-embedded tissues of mantle cell lymphomas by polymerase chain reaction.
Am J Clin Pathol
105:532, 1996[Medline]
[Order article via Infotrieve]
22.
Matlashewski GJ, Tuck S, Pim D, Lamb P, Schneider J, Crawford LV:
Primary structure polymorphism at amino acid residue 72 of human p53.
Mol Cell Biol
7:961, 1987[Abstract/Free Full Text]
23.
Baron BW, Nucifora G, McCabe N, Espinosa III, Le Beau MM, McKeithan TW:
Identification of the gene associated with the recurring chromosomal translocations t(3;14)(q27;q32) and t(3;22)(q27;q11) in B-cell lymphomas.
Proc Natl Acad Sci USA
90:5262, 1993[Abstract/Free Full Text]
24.
Boix J, Fibla J, Yuste V, Piulats JM, Llecha N, Comella JX:
Serum deprivation and protein synthesis inhibition induce two different apoptotic processes in N18 neuroblastoma cells.
Exp Cell Res
238:422, 1998[Medline]
[Order article via Infotrieve]
25.
Friend SH, Bernards R, Rogelj S, Weinberg RA, Rapaport JM, Albert DM, Dryja TP:
A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma.
Nature
323:643, 1986[Medline]
[Order article via Infotrieve]
26.
Wolfel T, Hauer M, Schneider J, Serrano M, Wolfel C, Klehmann-Hieb E, De Plaen E, Hankeln T, Meyer zum Buschenfelde KH, Beach D:
A p16ink4a-insensitive cdk4 mutant targeted by cytolytic T lymphocytes in a human melanoma.
Science
269:1281, 1995[Abstract/Free Full Text]
27.
Alkema MJ, Jacobs H, van Lohuizen M, Berns A:
Perturbation of B and T cell development and predisposition to lymphomagenesis in Emu bmi1 transgenic mice require the bmi1 ring finger.
Oncogene
15:899, 1997[Medline]
[Order article via Infotrieve]
28.
Kaplan GL, Meier P:
Non-parametric stimulation from incomplete observations.
J Am Stat Assoc
53:547, 1958
29.
Peto R, Pike MC:
Conservatism of the approximation sigma (O-E)2-E in the logrank test for survival data or tumor incidence data.
Biometrics
29:579, 1973[Medline]
[Order article via Infotrieve]
30.
Baron BW, Billstrand C, Madronero L, McKeithan TW:
HindIII polymorphism in the bcl6 gene.
Hum Mol Genet
2:1513, 1993[Free Full Text]
31.
Jares P, Campo E, Pinyol M, Bosch F, Miquel R, Fernandez PL, Sanchez-Beato M, Soler F, Perez-Losada A, Nayach I, Mallofre C, Piris MA, Montserrat E, Cardesa A:
Expression of retinoblastoma gene product (pRb) in mantle cell lymphomas. Correlation with cyclin D1 (PRAD1/CCND1) mRNA levels and proliferative activity.
Am J Pathol
148:1591, 1996[Abstract]
32.
Monni O, Oinonen R, Elonen E, Franssila K, Teerenhovi L, Joensuu H, Knuutila S:
Gain of 3q and deletion of 11q22 are frequent aberrations in mantle cell lymphoma.
Genes Chromosomes Cancer
21:298, 1998[Medline]
[Order article via Infotrieve]
33.
Dierlamm J, Rosenberg C, Stul M, Pittaluga S, Wlodarska I, Michaux L, Dehaen M, Verhoef G, Thomas J, de Kelver W, Bakker-Schut T, Cassiman JJ, Raap AK, De Wolf-Peeters C, Van den Berghe H, Hagemeijer A:
Characteristic pattern of chromosomal gains and losses in marginal zone B cell lymphoma detected by comparative genomic hybridization.
Leukemia
11:747, 1997[Medline]
[Order article via Infotrieve]
34.
Barth TFE, Döhner H, Werner CA, Stilgenbauer S, Schlotter M, Pawlita M, Lichter P, Möller P, Bentz M:
Characteristic pattern of chromosomal gains and losses in primary large B-cell lymphomas of the gastrointestinal tract.
Blood
91:4321, 1998[Abstract/Free Full Text]
35.
Bentz M, Dohner H, Huck K, Schutz B, Ganser A, Joos S, du Manoir S, Lichter P:
Comparative genomic hybridization in the investigation of myeloid leukemias.
Genes Chromosomes Cancer
12:193, 1995[Medline]
[Order article via Infotrieve]
36.
Chan WY, Wong N, Chan AB, Chow JH, Lee JC:
Consistent copy number gain in chromosome 12 in primary diffuse large cell lymphomas of the stomach.
Am J Pathol
152:11, 1998[Abstract]
37.
Joos S, Otano-Joos MI, Ziegler S, Bruderlein S, du Manoir S, Bentz M, Moller P, Lichter P:
Primary mediastinal (thymic) B-cell lymphoma is characterized by gains of chromosomal material including 9p and amplification of the rel gene.
Blood
87:1571, 1996[Abstract/Free Full Text]
38.
Karhu R, Knuutila S, Kallioniemi OP, Siltonen S, Aine R, Vilpo L, Vilpo J:
Frequent loss of the 11q14-24 region in chronic lymphocytic leukemia: A study by comparative genomic hybridization.
Genes Chromosomes Cancer
19:286, 1997[Medline]
[Order article via Infotrieve]
39.
Avet-Loiseau H, Vigier M, Moreau A, Mellerin MP, Gaillard F, Harousseau JL, Bataille R, Milpied N:
Comparative genomic hybridization detects genomic abnormalities in 80% of follicular lymphomas.
Br J Haematol
97:119, 1997[Medline]
[Order article via Infotrieve]
40.
Bentz M, Werner CA, Dohner H, Joos S, Barth TF, Siebert R, Schroder M, Stilgenbauer S, Fischer K, Moller P, Lichter P:
High incidence of chromosomal imbalances and gene amplifications in the classical follicular variant of follicle center lymphoma.
Blood
88:1437, 1996[Abstract/Free Full Text]
41.
Houldsworth J, Mathew S, Rao PH, Dyomina K, Louie DC, Parsa N, Offit K, Chaganti RS:
Rel proto-oncogene is frequently amplified in extranodal diffuse large cell lymphoma.
Blood
87:25, 1996[Abstract/Free Full Text]
42.
Monni O, Joensuu H, Franssila K, Klefstrom J, Alitalo K, Knuutila S:
Bcl2 overexpression associated with chromosomal amplification in diffuse large B-cell lymphoma.
Blood
90:1168, 1997[Abstract/Free Full Text]
43.
Monni O, Joensuu H, Franssila K, Knuutila S:
DNA copy number changes in diffuse large B-cell lymphoma.
Blood
87:5269, 1996[Abstract/Free Full Text]
44.
Cigudosa JC, Rao PH, Calasanz MJ, Odero MD, Michaeli J, Jhanwar SC, Chaganti RSK:
Characterization of nonrandom chromosomal gains and losses in multiple myeloma by comparative genomic hybridization.
Blood
91:3007, 1998[Abstract/Free Full Text]
45.
Juliusson G, Oscier DG, Fitchett M, Ross FM, Stockdill G, Mackie MJ, Parker AC, Castoldi GL, Cuneo A, Knuutila S, Elonen E, Gahrton G:
Prognostic subgroups in B-cell chronic lymphocytic defined by specific chromosomal abnormalities.
N Engl J Med
323:720, 1990[Abstract]
46.
Brown AG, Ross FM, Dunne EM, Steel CM, Weir-Thompson EM:
Evidence for a new tumour suppressor locus (dbm) in human B-cell neoplasia telomeric to the retinoblastoma gene.
Nat Genet
3:67, 1993[Medline]
[Order article via Infotrieve]
47.
Stilgenbauer S, Nickolenko J, Wilhelm J, Wolf S, Weitz S, Döhner K, Boehn T, Döhner H, Lichter P:
Expressed sequences as candidates for a novel tumor suppressor gene at band 13q14 in B-cell chronic lymphocytic leukemia and mantle cell lymphoma.
Oncogene
16:1891, 1998[Medline]
[Order article via Infotrieve]
48.
Ben-Yehuda D, Houldsworth J, Parsa NZ, Chaganti RS:
Gene amplification in non-Hodgkin's lymphoma.
Br J Haematol
86:792, 1994[Medline]
[Order article via Infotrieve]
49.
Werner CA, Dohner H, Joos S, Trumper LH, Baudis M, Barth TF, Ott G, Moller P, Lichter P, Bentz M:
High-level DNA amplifications are common genetic aberrations in B-cell neoplasms.
Am J Pathol
151:335, 1997[Abstract]
50.
Knuutila S, Bjorkqvist AM, Autio K, Tarkkanen M, Wolf M, Monni O, Szymanska J, Larramendy ML, Tapper J, Pere H, el-Rifai W, Hemmer S, Wasenius VM, Vidgren V, Zhu Y:
DNA copy number amplifications in human neoplasms: Review of comparative genomic hybridization studies.
Am J Pathol
152:1107, 1998[Abstract]
51.
Coquelle A, Pipiras E, Toledo F, Buttin G, Debatisse M:
Expression of fragile sites triggers intrachromosomal mammalian gene amplification and sets boundaries to early amplicons.
Cell
89:215, 1997[Medline]
[Order article via Infotrieve]
52.
Koduru PR, Raju K, Vadmal V, Menezes G, Shah S, Susin M, Kolitz J, Broome JD:
Correlation between mutation in p53, p53 expression, cytogenetics, histologic type, and survival in patients with B-cell non-Hodgkin's lymphoma.
Blood
90:4078, 1997[Abstract/Free Full Text]
53.
Campo E, de la Calle Martin O, Miquel R, Palacin A, Romero M, Fabregat V, Vives J, Cardesa A, Yague J:
Loss of heterozygosity of p53 gene and p53 protein expression in human colorectal carcinomas.
Cancer Res
51:4436, 1991[Abstract/Free Full Text]
54.
Khatib ZA, Matsushime H, Valentine M, Shapiro DN, Sherr CJ, Look AT:
Coamplification of the cdk4 gene with mdm2 and gli in human sarcomas.
Cancer Res
53:5535, 1993[Abstract/Free Full Text]
55.
Reifenberger G, Ichimura K, Reifenberger J, Elkahloun AG, Meltzer PS, Collins VP:
Refined mapping of 12q13-q15 amplicons in human malignant gliomas suggests cdk4/sas and mdm2 as independent amplification targets.
Cancer Res
56:5141, 1996[Abstract/Free Full Text]
56.
Rao PH, Houldsworth J, Dyomina K, Parsa NZ, Cigudosa JC, Louie DC, Popplewell L, Offit K, Jhanwar SC, Chaganti RS:
Chromosomal and gene amplification in diffuse large B-cell lymphoma.
Blood
92:234, 1998[Abstract/Free Full Text]
57.
Alkema MJ, Wiegant J, Raap AK, Berns A, van Lohuizen M:
Characterization and chromosomal localization of the human proto-oncogene bmi-1.
Hum Mol Genet
2:1597, 1993[Abstract/Free Full Text]
58.
Imamura J, Miyoshi I, Koeffler HP:
P53 in hematologic malignancies.
Blood
84:2412, 1994[Free Full Text]
59.
Pinyol M, Cobo F, Bea S, Jares P, Nayach I, Fernandez PL, Montserrat E, Cardesa A, Campo E:
p16INK4a gene inactivation by deletions, mutations, and hypermethylation is associated with transformed and aggressive variants of non-Hodgkin's lymphomas.
Blood
91:2977, 1998[Abstract/Free Full Text]
60.
Offit K, Jhanwar SC, Ladanyi M, Filippa DA, Chaganti RS:
Cytogenetic analysis of 434 consecutively ascertained specimens of non-Hodgkin's lymphoma: Correlations between recurrent aberrations, histology, and exposure to cytotoxic treatment.
Genes Chromosomes Cancer
3:189, 1991[Medline]
[Order article via Infotrieve]
61.
Richardson ME, Chen QG, Filippa DA, Offit K, Hampton A, Koduru PR, Jhanwar SC, Lieberman PH, Clarkson BD, Chaganti RS:
Intermediate- to high-grade histology of lymphomas carrying t(14;18) is associated with additional nonrandom chromosome changes.
Blood
70:444, 1987[Abstract/Free Full Text]
62.
Yunis JJ, Frizzera G, Oken MM, McKenna J, Theologides A, Arnesen M:
Multiple recurrent genomic defects in follicular lymphoma. A possible model for cancer.
N Engl J Med
316:79, 1987[Abstract]
63.
Garcia-Sanz R, Gonzalez M, Vargas M, Chillon MC, Balanzategui A, Barbon M, Flores MT, San Miguel JF:
Deletions and rearrangements of cyclin-dependent kinase 4 inhibitor gene p16 are associated with poor prognosis in B-cell non-Hodgkin's lymphomas.
Leukemia
11:1915, 1997[Medline]
[Order article via Infotrieve]
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
S. Bea, I. Salaverria, L. Armengol, M. Pinyol, V. Fernandez, E. M. Hartmann, P. Jares, V. Amador, L. Hernandez, A. Navarro, et al.
Uniparental disomies, homozygous deletions, amplifications, and target genes in mantle cell lymphoma revealed by integrative high-resolution whole-genome profiling
Blood,
March 26, 2009;
113(13):
3059 - 3069.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Hartmann, V. Fernandez, V. Moreno, J. Valls, L. Hernandez, F. Bosch, P. Abrisqueta, W. Klapper, M. Dreyling, E. Hoster, et al.
Five-Gene Model to Predict Survival in Mantle-Cell Lymphoma Using Frozen or Formalin-Fixed, Paraffin-Embedded Tissue
J. Clin. Oncol.,
October 20, 2008;
26(30):
4966 - 4972.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Bea and E. Campo
Secondary genomic alterations in non-Hodgkin's lymphomas: tumor-specific profiles with impact on clinical behavior
Haematologica,
May 1, 2008;
93(5):
641 - 645.
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Sander, L. Bullinger, E. Leupolt, A. Benner, D. Kienle, T. Katzenberger, J. Kalla, G. Ott, H. K. Muller-Hermelink, T. F.E. Barth, et al.
Genomic aberrations in mantle cell lymphoma detected by interphase fluorescence in situ hybridization. Incidence and clinicopathological correlations
Haematologica,
May 1, 2008;
93(5):
680 - 687.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Kienle, T. Katzenberger, G. Ott, D. Saupe, A. Benner, H. Kohlhammer, T. F.E. Barth, S. Holler, J. Kalla, A. Rosenwald, et al.
Quantitative Gene Expression Deregulation in Mantle-Cell Lymphoma: Correlation With Clinical and Biologic Factors
J. Clin. Oncol.,
July 1, 2007;
25(19):
2770 - 2777.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Pinyol, S. Bea, L. Pla, V. Ribrag, J. Bosq, A. Rosenwald, E. Campo, and P. Jares
Inactivation of RB1 in mantle-cell lymphoma detected by nonsense-mediated mRNA decay pathway inhibition and microarray analysis
Blood,
June 15, 2007;
109(12):
5422 - 5429.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Ripperger, N. von Neuhoff, K. Kamphues, M. Emura, U. Lehmann, M. Tauscher, M. Schraders, P. Groenen, B. Skawran, C. Rudolph, et al.
Promoter methylation of PARG1, a novel candidate tumor suppressor gene in mantle cell lymphomas
Haematologica,
April 1, 2007;
92(4):
460 - 468.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. Salaverria, A. Zettl, S. Bea, V. Moreno, J. Valls, E. Hartmann, G. Ott, G. Wright, A. Lopez-Guillermo, W. C. Chan, et al.
Specific Secondary Genetic Alterations in Mantle Cell Lymphoma Provide Prognostic Information Independent of the Gene Expression-Based Proliferation Signature
J. Clin. Oncol.,
April 1, 2007;
25(10):
1216 - 1222.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Mestre-Escorihuela, F. Rubio-Moscardo, J. A. Richter, R. Siebert, J. Climent, V. Fresquet, E. Beltran, X. Agirre, I. Marugan, M. Marin, et al.
Homozygous deletions localize novel tumor suppressor genes in B-cell lymphomas
Blood,
January 1, 2007;
109(1):
271 - 280.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Pscherer, J. Schliwka, K. Wildenberger, A. Mincheva, C. Schwaenen, H. Dohner, S. Stilgenbauer, and P. Lichter
Antagonizing inactivated tumor suppressor genes and activated oncogenes by a versatile transgenesis system: application in mantle cell lymphoma
FASEB J,
June 1, 2006;
20(8):
1188 - 1190.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. M. Rimsza, R. A. Roberts, E. Campo, T. M. Grogan, S. Bea, I. Salaverria, A. Zettl, A. Rosenwald, G. Ott, H. K. Muller-Hermelink, et al.
Loss of major histocompatibility class II expression in non-immune-privileged site diffuse large B-cell lymphoma is highly coordinated and not due to chromosomal deletions
Blood,
February 1, 2006;
107(3):
1101 - 1107.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Bea, A. Zettl, G. Wright, I. Salaverria, P. Jehn, V. Moreno, C. Burek, G. Ott, X. Puig, L. Yang, et al.
Diffuse large B-cell lymphoma subgroups have distinct genetic profiles that influence tumor biology and improve gene-expression-based survival prediction
Blood,
November 1, 2005;
106(9):
3183 - 3190.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Rubio-Moscardo, J. Climent, R. Siebert, M. A. Piris, J. I. Martin-Subero, I. Nielander, J. Garcia-Conde, M. J. S. Dyer, M. J. Terol, D. Pinkel, et al.
Mantle-cell lymphoma genotypes identified with CGH to BAC microarrays define a leukemic subgroup of disease and predict patient outcome
Blood,
June 1, 2005;
105(11):
4445 - 4454.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Hernandez, S. Bea, M. Pinyol, G. Ott, T. Katzenberger, A. Rosenwald, F. Bosch, A. Lopez-Guillermo, J. Delabie, D. Colomer, et al.
CDK4 and MDM2 Gene Alterations Mainly Occur in Highly Proliferative and Aggressive Mantle Cell Lymphomas with Wild-type INK4a/ARF Locus
Cancer Res.,
March 15, 2005;
65(6):
2199 - 2206.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Schraders, R. Pfundt, H. M. P. Straatman, I. M. Janssen, A. G. van Kessel, E. F. P. M. Schoenmakers, J. H. J. M. van Krieken, and P. J. T. A. Groenen
Novel chromosomal imbalances in mantle cell lymphoma detected by genome-wide array-based comparative genomic hybridization
Blood,
February 15, 2005;
105(4):
1686 - 1693.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Iranzo, I. Lopez, M. T. Robles, J. M. Mascaro Jr, E. Campo, and C. Herrero
Bullous Pemphigoid Associated With Mantle Cell Lymphoma
Arch Dermatol,
December 1, 2004;
140(12):
1496 - 1499.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Bea, L. Colomo, A. Lopez-Guillermo, I. Salaverria, X. Puig, M. Pinyol, S. Rives, E. Montserrat, and E. Campo
Clinicopathologic Significance and Prognostic Value of Chromosomal Imbalances in Diffuse Large B-Cell Lymphomas
J. Clin. Oncol.,
September 1, 2004;
22(17):
3498 - 3506.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. J. de Leeuw, J. J. Davies, A. Rosenwald, G. Bebb, R. D. Gascoyne, M. J.S. Dyer, L. M. Staudt, J. A. Martinez-Climent, and W. L. Lam
Comprehensive whole genome array CGH profiling of mantle cell lymphoma model genomes
Hum. Mol. Genet.,
September 1, 2004;
13(17):
1827 - 1837.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Kohlhammer, C. Schwaenen, S. Wessendorf, K. Holzmann, H. A. Kestler, D. Kienle, T. F. E. Barth, P. Moller, G. Ott, J. Kalla, et al.
Genomic DNA-chip hybridization in t(11;14)-positive mantle cell lymphomas shows a high frequency of aberrations and allows a refined characterization of consensus regions
Blood,
August 1, 2004;
104(3):
795 - 801.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Martinez, B. Bellosillo, F. Bosch, A. Ferrer, S. Marce, N. Villamor, G. Ott, E. Montserrat, E. Campo, and D. Colomer
Nuclear Survivin Expression in Mantle Cell Lymphoma Is Associated with Cell Proliferation and Survival
Am. J. Pathol.,
February 1, 2004;
164(2):
501 - 510.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Martinez, F. I. Camacho, P. Algara, A. Rodriguez, A. Dopazo, E. Ruiz-Ballesteros, P. Martin, J. A. Martinez-Climent, J. Garcia-Conde, J. Menarguez, et al.
The Molecular Signature of Mantle Cell Lymphoma Reveals Multiple Signals Favoring Cell Survival
Cancer Res.,
December 1, 2003;
63(23):
8226 - 8232.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Kienle, A. Krober, T. Katzenberger, G. Ott, E. Leupolt, T. F. E. Barth, P. Moller, A. Benner, A. Habermann, H. K. Muller-Hermelink, et al.
VH mutation status and VDJ rearrangement structure in mantle cell lymphoma: correlation with genomic aberrations, clinical characteristics, and outcome
Blood,
October 15, 2003;
102(8):
3003 - 3009.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Orchard, R. Garand, Z. Davis, G. Babbage, S. Sahota, E. Matutes, D. Catovsky, P. W. Thomas, H. Avet-Loiseau, and D. Oscier
A subset of t(11;14) lymphoma with mantle cell features displays mutated IgVH genes and includes patients with good prognosis, nonnodal disease
Blood,
June 15, 2003;
101(12):
4975 - 4981.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Sanchez-Izquierdo, G. Buchonnet, R. Siebert, R. D. Gascoyne, J. Climent, L. Karran, M. Marin, D. Blesa, D. Horsman, A. Rosenwald, et al.
MALT1 is deregulated by both chromosomal translocation and amplification in B-cell non-Hodgkin lymphoma
Blood,
June 1, 2003;
101(11):
4539 - 4546.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. I. Camacho, P. Algara, A. Rodriguez, E. Ruiz-Ballesteros, M. Mollejo, N. Martinez, J. A. Martinez-Climent, M. Gonzalez, M. Mateo, A. Caleo, et al.
Molecular heterogeneity in MCL defined by the use of specific VH genes and the frequency of somatic mutations
Blood,
May 15, 2003;
101(10):
4042 - 4046.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. A. Martinez-Climent, A. A. Alizadeh, R. Segraves, D. Blesa, F. Rubio-Moscardo, D. G. Albertson, J. Garcia-Conde, M. J. S. Dyer, R. Levy, D. Pinkel, et al.
Transformation of follicular lymphoma to diffuse large cell lymphoma is associated with a heterogeneous set of DNA copy number and gene expression alterations
Blood,
April 15, 2003;
101(8):
3109 - 3117.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Tort, S. Hernandez, S. Bea, A. Martinez, M. Esteller, J. G. Herman, X. Puig, E. Camacho, M. Sanchez, I. Nayach, et al.
CHK2-decreased protein expression and infrequent genetic alterations mainly occur in aggressive types of non-Hodgkin lymphomas
Blood,
December 15, 2002;
100(13):
4602 - 4608.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Viardot, P. Moller, J. Hogel, K. Werner, G. Mechtersheimer, A. D. Ho, G. Ott, T. F.E. Barth, R. Siebert, S. Gesk, et al.
Clinicopathologic Correlations of Genomic Gains and Losses in Follicular Lymphoma
J. Clin. Oncol.,
December 1, 2002;
20(23):
4523 - 4530.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Zettl, G. Ott, A. Makulik, T. Katzenberger, P. Starostik, T. Eichler, B. Puppe, M. Bentz, H. K. Muller-Hermelink, and A. Chott
Chromosomal Gains at 9q Characterize Enteropathy-Type T-Cell Lymphoma
Am. J. Pathol.,
November 1, 2002;
161(5):
1635 - 1645.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Bea, A. Lopez-Guillermo, M. Ribas, X. Puig, M. Pinyol, A. Carrio, L. Zamora, F. Soler, F. Bosch, S. Stilgenbauer, et al.
Genetic Imbalances in Progressed B-Cell Chronic Lymphocytic Leukemia and Transformed Large-Cell Lymphoma (Richter's Syndrome)
Am. J. Pathol.,
September 1, 2002;
161(3):
957 - 968.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Korz, A. Pscherer, A. Benner, D. Mertens, C. Schaffner, E. Leupolt, H. Dohner, S. Stilgenbauer, and P. Lichter
Evidence for distinct pathomechanisms in B-cell chronic lymphocytic leukemia and mantle cell lymphoma by quantitative expression analysis of cell cycle and apoptosis-associated genes
Blood,
May 29, 2002;
99(12):
4554 - 4561.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. O. Ness, H. Lybak, J. Arnes, and E. Rodahl
Chromosomal Imbalances in Lymphoid Tumors of the Orbit
Invest. Ophthalmol. Vis. Sci.,
January 1, 2002;
43(1):
9 - 14.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. P. Otte and M. van Lohuizen
Correspondence re: S. Bea et al., BMI-1 Gene Amplification and Overexpression in Hematological Malignancies Occur Mainly in Mantle Cell Lymphomas. Cancer Res., 61: 2409-2412, 2001
Cancer Res.,
January 1, 2002;
62(2):
618 - 618.
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Camacho, L. Hernandez, S. Hernandez, F. Tort, B. Bellosillo, S. Bea, F. Bosch, E. Montserrat, A. Cardesa, P. L. Fernandez, et al.
ATM gene inactivation in mantle cell lymphoma mainly occurs by truncating mutations and missense mutations involving the phosphatidylinositol-3 kinase domain and is associated with increasing numbers of chromosomal imbalances
Blood,
January 1, 2002;
99(1):
238 - 244.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. A. Martinez-Climent, E. Vizcarra, D. Sanchez, D. Blesa, I. Marugan, I. Benet, F. Sole, F. Rubio-Moscardo, M. J. Terol, J. Climent, et al.
Loss of a novel tumor suppressor gene locus at chromosome 8p is associated with leukemic mantle cell lymphoma
Blood,
December 1, 2001;
98(12):
3479 - 3482.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. J. van Kemenade, F. M. Raaphorst, T. Blokzijl, E. Fieret, K. M. Hamer, D. P. E. Satijn, A. P. Otte, and C. J. L. M. Meijer
Coexpression of BMI-1 and EZH2 polycomb-group proteins is associated with cycling cells and degree of malignancy in B-cell non-Hodgkin lymphoma
Blood,
June 15, 2001;
97(12):
3896 - 3901.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. M. Hernandez, J. L. Garcia, N. C. Gutierrez, M. Mollejo, J. A. Martinez-Climent, T. Flores, M. B. Gonzalez, M. A. Piris, and J. F. San Miguel
Novel Genomic Imbalances in B-Cell Splenic Marginal Zone Lymphomas Revealed by Comparative Genomic Hybridization and Cytogenetics
Am. J. Pathol.,
May 1, 2001;
158(5):
1843 - 1850.
[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]
|
|
|
|
|
|
|
S. Beà, F. Tort, M. Pinyol, X. Puig, L. Hernández, S. Hernández, P. L. Fernández, M. van Lohuizen, D. Colomer, and E. Campo
BMI-1 Gene Amplification and Overexpression in Hematological Malignancies Occur Mainly in Mantle Cell Lymphomas
Cancer Res.,
March 1, 2001;
61(6):
2409 - 2412.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
F. M. Raaphorst, F. J. van Kemenade, T. Blokzijl, E. Fieret, K. M. Hamer, D. P. E. Satijn, A. P. Otte, and C. J. L. M. Meijer
Coexpression of BMI-1 and EZH2 Polycomb Group Genes in Reed-Sternberg Cells of Hodgkin's Disease
Am. J. Pathol.,
September 1, 2000;
157(3):
709 - 715.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Pinyol, L. Hernandez, A. Martinez, F. Cobo, S. Hernandez, S. Bea, A. Lopez-Guillermo, I. Nayach, A. Palacin, A. Nadal, et al.
INK4a/ARF Locus Alterations in Human Non-Hodgkin's Lymphomas Mainly Occur in Tumors with Wild-Type p53 Gene
Am. J. Pathol.,
June 1, 2000;
156(6):
1987 - 1996.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Voncken, D Schweizer, L Aagaard, L Sattler, M. Jantsch, and M van Lohuizen
Chromatin-association of the Polycomb group protein BMI1 is cell cycle-regulated and correlates with its phosphorylation status
J. Cell Sci.,
January 12, 1999;
112(24):
4627 - 4639.
[Abstract]
[PDF]
|
|
|
|
|
|
|
C. Schaffner, I. Idler, S. Stilgenbauer, H. Dohner, and P. Lichter
Mantle cell lymphoma is characterized by inactivation of the ATM gene
PNAS,
March 14, 2000;
97(6):
2773 - 2778.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
TOP
ABSTRACT
INTRODUCTION