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Blood, Vol. 93 No. 4 (February 15), 1999:
pp. 1372-1380
Cytogenetic Profile of Lymphoma of Follicle Mantle Lineage:
Correlation With Clinicobiologic Features
By
Antonio Cuneo,
Renato Bigoni,
Gian Matteo Rigolin,
Maria Grazia Roberti,
Antonella Bardi,
Nadia Piva,
Raffaella Milani,
Florencia Bullrich,
Maria Luisa Veronese,
Carlo Croce,
Françoise Birg,
Hartmut Döhner,
Anne Hagemeijer, and
Gianluigi Castoldi
From the Department of Biomedical Sciences-Hematology Section,
University of Ferrara, Italy; Kimmel Cancer Center, Thomas Jefferson
University, Philadelphia, PA; Ruprecht-Karls-Universitat, Medizinische
Klinik und Poliklinik V, Heidelberg, Germany; Institut de
Cancérologie e d'Immunologie de Marseille, INSERM 119, Marseille, France; and the Centre for Human Genetic, K.U.L., Leuven,
Belgium.
 |
ABSTRACT |
Conventional chromosome analysis (CCA) and interphase fluorescence
in situ hybridization (FISH) was performed in 42 patients with
mantle-cell lymphoma (MCL), with BCL1 rearrangement. The t(11;14)(q13;q32) or 11q abnormalities were detected by CCA in 34 cases, 20 of which had additional aberrations. A normal karyotype was
observed in 8 cases. Probes detecting the chromosome aberrations that
were observed in at least 3 cases by CCA, ie, +12, 13q14 deletion,
and 17p deletion, were used for interphase FISH analysis. FISH detected
total or partial +12, 13q14 deletion and 17p- in 28.5%, 52.4%, and
26% of the cases, respectively. The presence of these anomalies was
not a function of karyotype complexity. Based on the results of
CCA/FISH, three groups of increasing karyotype complexity were
recognized: group 1, including 11 patients without detectable
aberrations in addition to BCL1 rearrangement; group 2, including 14 patients with 1 to 2 additional anomalies; and group 3, including 17 patients with three or more additional anomalies. Clinical
parameters associated with shorter survival were male sex (P
= .006) and primary lymph-node involvement compared with primary bone
marrow involvement (P = .015). Trisomy 12 was the only single cytogenetic parameter predictive of a poor prognosis (P = .006) and the best prognostic indicator was the derived
measure of karyotype complexity (P < .0001), which maintained
statistical significance in multivariate analysis (P< .0001).
We arrived at the following conclusions: 13q14 deletion occurs at a
high incidence in MCL; 17p deletion and total/partial +12 are
relatively frequent events in MCL, the latter aberration being
associated with a shorter survival; and the degree of karyotype
complexity has a strong impact on prognosis in this neoplasia.
© 1999 by The American Society of Hematology.
 |
INTRODUCTION |
USING SENSITIVE MOLECULAR cytogenetic
techniques, the majority of cases of lymphoma of follicle mantle
lineage were shown to carry the 11;14 translocation1-4 and
its molecular counterpart, consisting of the juxtaposition of the
BCL1 locus and the immunoglobulin heavy-chain locus on the
derivative 14q+ chromosome.5-7 This disease, which was
recognized as a distinct clinicopathological entity as early as
1982,8 accounts for 3% to 9% of all non-Hodgkin's lymphomas (NHL) in western countries.9 It more frequently
affects middle-aged to elderly males, who usually have advanced disease involving lymph nodes and spleen as well as extranodal sites, especially the gastrointestinal (GI) tract and the bone marrow (BM).
Frequently, peripheral blood (PB) involvement also occurs, either
during disease evolution10 or at diagnosis, mimicking chronic lymphocytic leukemia (CLL).11
Although a number of hematologic and biologic variables were shown to
have correlation with survival in MCL,9,12,13 there is
interstudy variability as to the prognostic significance of each of
these variables,13-17 partially on account of the limited number of cases studied and of the heterogeneity of patient population.
There is evidence that genetic lesions may help identify prognostically
different subgroups of NHL.18-20 Thus, p53 lesions were
reproducibly associated with aggressive disease in MCL21,22 and in B-cell CLL,23 as was the case with chromosome 17p
deletions20,24,25 and aberrations of chromosomes 1, 6, and
1120,26,27 that were found to have prognostic significance
in several subtypes of NHL.
In an attempt to better define the incidence and nature of chromosome
lesions in MCL and to disclose cytogenetic patterns having prognostic
significance, we identified 42 patients with BCL1 involvement
and performed conventional cytogenetic analysis (CCA), that identified
13q14 deletion, 17p- and trisomy 12q as the most frequently occurring
aberrations in addition to the t(11;14)(q13;q32). These chromosome
lesions were subsequently investigated by the more-sensitive interphase
fluorescence in situ hybridization (FISH) technique and an analysis was
performed of the correlation between these chromosome lesions and
salient hematologic parameters.
 |
MATERIALS AND METHODS |
Patients and clinical parameters.
Fifty-nine patients with non-Hodgkin's lymphoma (NHL) of follicle
mantle lineage were diagnosed at the Institute of Hematology, University of Ferrara (Ferrara, Italy), over a 10-year period. Histologic diagnosis was performed according to recently summarized criteria9,28,29 on lymph-node specimens and/or
bone-biopsy sections.
Of these 59 patients, 42 cases fulfilling the following criteria were
included in the present study: (1) karyotype available for review. (2)
Presence of the t(11;14) (q13;q32), or the corresponding BCL1
involvement as detected by FISH technique on representative lymph-node or PB samples. FISH was shown in previous studies to be a
very sensitive method for the detection of rearrangements occurring in
the BCL1 locus.2,3 (3) Histologic picture of MCL on
lymph-node specimens (28 cases with primary lymph-node involvement); or
bone biopsy sections consistent with infiltration by MCL (14 patients
with primary involvement of the BM and PB who had no superficial
adenopathy available for biopsy). (4) Mantle-cell immunophenotype in
cases with leukemic expression, ie, CD5/CD19+,
CD22+, CD23 , CD10 ,
and bright expression of surface immunoglobulins (sIg). Other forms of
NHL, CLL, and related disorders (ie, CLL/PL and prolymphocytic leukemia) as well as other chronic (mature) B-cell lymphoproliferative disorders30 were excluded from this analysis, irrespective
of the presence of the t(11;14).
Staging procedures included physical examination, a routine laboratory
profile, a chest radiograph, and abdomen ultrasonography. When
indicated, barium contrast radiography was performed. Computed tomography (CT) scan was performed for staging purposes in
32 cases, bone biopsy was performed in 34 cases (including 14 cases with primary BM involvement). BM aspiration was performed
in all cases. PB involvement was studied by light microscopy
examination of smears stained by the May-Grunwald-Giemsa method and by
immunophenotyping using the following panel of commercially available
monoclonal antibodies: anti CD2, CD3, CD5, CD19, CD22, CD23, CD10, and
FMC7. Double labeling with anti-CD5/CD19 was performed and the
expression of sIg was studied using rabbit antihuman antibodies against
the Ig heavy and light chains as previously reported.31
Treatment was not homogeneous. Depending on age, stage, performance
status, and on the clinical course the following first-line treatments
were used: single-agent therapy (chlorambucil) in 10 cases and
multiagent chemotherapy using cyclophosphamide, vincristine, and
prednisone, with (26 cases) or without (6 cases) an anthracycline.
Clinical records were surveyed for all cases and the parameters
outlined in Table 1 were collected.
CCA.
Cytogenetic investigations were performed on lymph-node and/or
PB samples obtained within 3 months of diagnosis in all patients. Single-cell suspensions were prepared, as previously
described,32 after collection of a portion of surgically
removed lymph node (28 cases, 6 of which were also studied on PB
samples), and on PB mononuclear cells obtained by separation over a
1,077 mg/mL density gradient in 14 cases with prominent leukemic
involvement. PB and lymph-node cell suspensions containing greater than
90% CD5/CD19+ lymphocytes were cultured for 24 to 72 hours, with and without the following mitogens: phorbol miristate
acetate (50 ng/mL), lipopolysaccaride from Escherichia
coli (100 mg/mL), and phytohemagglutinin M-form (100 mg/mL). Whenever possible, 20 to 30 metaphases were studied and
karyotypes described according to the ISCN.33
Interphase cytogenetics.
Interphase FISH studies were performed using probes detecting BCL1
rearrangements and those chromosome lesions that were found in at least
three patients by CCA. These studies were performed on cells taken from
the same samples that were used for cytogenetic analysis.
BCL1 involvement was documented as previously
reported,34 using the yeast-artificial-chromosome (YAC)
probe 214D11, spanning a 390 kb region encompassing the major
translocation cluster and the minor translocation clusters of the
BCL1 locus at 11q13.35 The presence of three
signals in interphase cells (one deriving from the normal allele and
two deriving from the split BCL1 allele) was considered
indicative of BCL1 involvement. To prevent data misinterpretation due to the presence of trisomy or monosomy 11, a
chromosome 11-specific centromeric probe (Oncor, Gaithersburg, MD), or
the cosmid cCI11-395, located at 11p15.5, which was obtained from the
Japanese Cancer Research Resources Bank,3 were used as
control probes. To document the juxtaposition of BCL1/14q
sequences, dual-color FISH was performed in those cases without
cytogenetic evidence of the t(11;14), using the BCL1 probe and
a 14q telomere probe, or the cos a2 IgH constant-region probe (prepared
by H. Dohner, Ruprecht-Karls-Universitat, Medizinische Klinik und
Poliklinik V, Heidelberg, Germany) because deletions of 13q, 17p, and
total or partial trisomy 12 were the most frequent abnormalities in addition to the 11;14 translocation, having been found in at least 3 cases. Probes for the detection of these anomalies in interphase cells
were used to increase the sensitivity of our analysis. The 13q14 C21
cosmid, recognizing DNA sequences between the Rb gene and the D13S25
marker,36 was isolated as previously
described.34 Simultaneous hybridization with a chromosome
13-telomere probe (Oncor) was performed. The p53.3 cosmid recognizing
p53 gene sequences at the 17p13 chromosome band was prepared and
distributed by H. Döhner through F. Birg (Institut de
Cancérologie e d'Immunologie de Marseille, INSERM 119, Marseille, France) in the context of the Biomed I programme, "E.U.
concerted action for cytogenetic diagnosis of hematologic
malignancies" (Project leader: A. Hagemeijer, Centre for Human
Genetic, K.U.L., Leuven, Belgium). Simultaneous hybridization with a
chromosome 17-centromeric probe was performed (Oncor). A commercially
available chromosome 12-pericentromeric probe was used for the
detection of total/partial trisomy 12 (Oncor).
Hybridization and signal screening.
The hybridization protocol was described in detail in previous
studies.3,34 To prevent false-positive results due to
inefficient hybridization, signal screening was performed on slides
with a high hybridization efficiency, having greater than 80%
interphase cells showing two signals with the control probe. The
evaluation was performed on a fluorescence microscope (Nikon Italia,
Florence, Italy); 200 cells with well-delineated signals were observed
and images were captured with a charged-coupled camera device
(Genevision, Nikon Italia).
Five control slides obtained from non-neoplastic tissue were tested
with each probe. The cut off for the recognition of BCL1 involvement and +12 was set at 5% interphase cells with 3 signals, whereas greater than 10% cells with 1 signal were required for the
recognition of 13q14 deletion and 17p13 deletion.
Cytogenetic classification.
To analyze the correlation of cytogenetic data and clinicobiologic
findings, three cytogenetic groups were identified based on the number
of chromosome lesions as detected by CCA and interphase FISH. Group 1, including those BCL1-rearranged patients with a normal
karyotype in at least 20 metaphases and those patients with the
t(11;14) as the sole change. Group 2, including patients with 1 to 2 aberrations in addition to the t(11;14)/BCL1 rearrangement, and
Group 3, defined by those patients with three or more aberrant events
in addition to the t(11;14).
Statistical analysis.
Analysis of variance (ANOVA) with Bonferroni correction for multiple
comparisons was used in the analysis of continuous variables whereas
2 test was applied for categorical variables. Patient
survival was estimated by the Kaplan-Meier method from the date of
diagnosis until death due to any cause or until the last patient
follow-up. The survival curves were statistically compared by the
log-rank test. Because many statistical tests were undertaken in the
evaluation of prognosis, a P value of .02 was used as the
criterion for statistical significance. Proportional hazards regression
analysis was used to identify the most significant independent
prognostic variables on survival. P values less than .05 were
considered statistically significant.
 |
RESULTS |
Chromosome lesions: CCA and FISH.
All cases had BCL1 involvement in the area covered by the 390kb
YAC probe (Fig 1), resulting in
the presence of three signals in 41% to 97% of the interphase cells
(median value 73%). The t(11;14)(q13;q32) was documented by chromosome
banding in a total of 29 cases, 15 of which had additional aberrations,
rearrangements of 11q with complex karyotypes were observed in 5 patients and a normal karyotype was observed at diagnosis in 8 patients. Results are detailed in Table 2.

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| Fig 1.
BCL1 rearranged leukemic MCL with primary BM
involvement. Note the heterogeneity of cell size and morphology with
irregular nuclear outline (left). A cell showing juxtaposition
(arrowed) of BCL1 (green) to IgH (red) sequences is shown on the right.
|
|
Additional chromosome changes observed in three or more cases were loss
of chromosome material at 13q and 17p- and total or partial trisomy 12. Monosomy 13 and structural 13q14 aberrations were detected by CCA in
six cases. FISH documented the presence of 13q14 deletion in these
cases and disclosed cytogenetically undetected 13q14 deletion in 16 additional cases (percentage of cells with one signal 64% to 90%).
Three patients had total/partial trisomy 12 at banding analysis and
nine additional patients were shown to carry extra chromosome 12 material in 28% to 68% of the cells by interphase FISH. Three
patients had deletion 17p at metaphase banding analysis;
cytogenetically undetected 17p13 deletions in 38% to 88% interphase
nuclei were observed in eight additional cases. The frequency of these
chromosome lesions in patients with complex karyotype (ie, patients
with three or more aberrations in addition to the 11;14 translocation)
compared with patients with noncomplex karyotype was as follows: 8 of
14 versus 14 of 28 for 13q14 deletion (P = 0.662); 5 of 14 versus 7 of 28 for +12 (P = .469) and 6 of 14 versus 5 of 28 for 17p- (P = .082).
The composition of cytogenetic groups 1, 2, 3 was the following (see
Table 2): using data obtained by CCA, 22 patients had the t(11;14) as
the sole change or a normal karyotype in more than 20 metaphases (group
1), 6 patients had one to two additional chromosome changes (group 2)
and 14 patients had three or more additional aberrant events (group 3);
when considering CCA plus interphase cytogenetic findings, 11 patients
were found to have no detectable chromosome lesions in addition to the
t(11;14)/BCL1 involvement (group 1), 14 patients had one to two
additional aberrations (group 2) and 17 patients had three or more
additional aberrations (group 3).
Hematologic and clinical features.
The salient hematologic features at presentation are summarized in
Table 1. Primary sites of disease involvement at presentation were the
lymph-node system in 28 cases, whereas the BM and PB (with or without
splenomegaly) were primarily involved in 14 patients. Globally,
extranodal involvement of the BM, spleen, gastrointestinal tract and
Waldeyer's ring occurred at presentation in 66% of the cases.
BM involvement usually consisted of interstitial or intertrabecular
infiltrates of small- to medium-sized lymphocytes, with round-to-oval
nuclei and nuclear indentations. Leukemic expression was found in 31 of
42 cases, having 10% to 98% CD5/C19+ cells in the
lymphocyte gate (absolute lymphocyte count ranging between 1 and 800 × 109/L, median 22.4 × 109/L). The
morphology of these cells showed heterogeneity of cell size and
irregularities of nuclear outline (Fig 1); some small lymphocytes
indistinguishable from CLL cells and prolymphocyte-like cells were also
present. All cases with leukemic expression were CD5/CD19+,
CD22+, FMC7+, CD23 , and
CD10 and sIg+ with a bright pattern of
expression and surface / restriction.
Thirteen patients are alive at 12 to 79 months, with a median follow-up
of 36 months, whereas 29 died at 2 to 86 months. Median overall
survival in this series was 40 and 34 months in the less than 60 and
greater than 60 year age groups, respectively.
Survival.
The correlation of clinical outcome and clinicobiologic parameters is
summarized in Table 3, showing that male
sex and primary lymph-node involvement were predictive of a shorter
survival, whereas age, LDH level, advanced stage at presentation, serum albumin level, PB/BM involvement, PS, and splenomegaly were not. Trisomy 12 as detected by FISH was the only single cytogenetic parameter having prognostic significance
(Fig 2), however the strongest prognostic
indicator of shorter survival in univariate analysis was the degree of
karyotype complexity (Table 3 and Fig 3).
Except for male sex, which was associated with complex karyotype, the
distribution of other salient clinical and hematologic parameters did
not show any statistically significant correlation with cytogenetic
features, as summarized in Table 4. Few
patients presented blastic morphology or a nodular pattern
of growth in lymph-node specimens (Table 1), precluding a meaningful
analysis of the correlation of these histologic parameters with
cytogenetic patterns.
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Table 3.
Outcome According to Clinical and Biological
Parameters in 42 Patients With t(11;14): Uniparameter Analysis
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| Fig 2.
Survival according to the presence (n = 12) or absence
(n = 30) of total/partial trisomy 12 (P .006).
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| Fig 3.
Survival according to the degree of karyotype complexity
as defined by CCA + FISH analysis (group 1 = 11 patients; group 2 = 14 patients; group 3 = 17 patients) (P < .0001).
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The Cox regression model for survival showed that among the
above-reported variables having prognostic significance in univariate analysis, only the measure of karyotype complexity as assessed by FISH
and CCA maintained prognostic significance, with a P < .0001 (4,7805 hazard ratio; 2.2884 to 9.9874, 95% confidence limits).
 |
DISCUSSION |
A preliminary methodological problem in this study was represented by
the definition of the inclusion criteria, given the heterogeneity of clinicopathological manifestations of
MCL.9,12,21,37 Because lymphoma of follicle mantle lineage
have in common a specific genetic marker and the immunophenotypic
profile,9 we included patients with the
t(11;14)/BCL1 rearrangement and with cytoimmunologic features
characteristic of MCL. These biological markers of MCL were
particularly important in distinguishing those cases presenting with
primary BM and PB involvement from other leukemic NHL and chronic
B-cell disorders, which may present similar morphologic features.
Inclusion criteria in this series accounted on the one hand for the
absence of cases with primary extranodal disease, all biopsy material
from extranodal sites having been sent to the pathologist for
histologic diagnosis and, on the other hand, for the relatively high
number of cases with primary BM involvement and leukemic expression.
Other hematologic features in our patients (Tables 1 and 3) did not
differ significantly as compared with those reported in recent
studies,12,13,15,16 with frequent presentation in advanced
stage (74% of the cases, compared with 77% to 91%), male sex
preponderance (2:1 compared with 1.6:1 up to 3:1), relatively
old age (68 years, compared with 62 to 65 years) and short survival (34 and 40 months in the greater than 60 and less than 60 year
age groups, compared with 43 to 56 months median overall survival). The
histologic features, with a majority of cases presenting diffuse
infiltration pattern and few cases displaying a predominantly blastic
morphology, are in line with previous observations.12
The overall cytogenetic picture and the chromosome lesions that were
found in this series in addition to BCL1
involvement/t(11;14)(q13;q32) improve our knowledge on the
clinicobiologic significance of cytogenetics in MCL, showing that
total/partial trisomy 12 and a derived measure of karyotype complexity
may have a correlation with survival. 13q14 deletion, total or partial
trisomy 12, and 17p13 deletion occurred at a relatively high frequency
in this series and were not simply a function of karyotype complexity,
suggesting that these anomalies are acquired early during the
cytogenetic evolution of MCL.
We found a relatively high incidence of normal karyotype (19%) and
isolated t(11;14) (33%) in newly diagnosed BCL1+
MCL. These findings add to the data by Pittaluga et al29
who described a 55% and 8% incidence of normal karyotype and t(11;14) as the sole change, respectively, in 38 cases and with the data collected by Johansson et al,38 who presented a 19.8%
incidence of isolated t(11;14) in 91 cases published in the literature. FISH studies,39 however, showed that cytogenetic findings
in MCL are partially influenced by suboptimal culture conditions and
inadequate banding resolution, having three consequences: (1) detection
of normal karyotypes due to divisions occurring in residual normal
lymphocytes; (2) detection of the primary chromosome change defining
the stemline with failure to show additional anomalies present in the
sidelines; and (3) impossibility to recognize subtle rearrangements,
especially small deletions, occurring in the context of abnormal
karyotypes. Point 1 is illustrated in our study by eight BCL1
rearranged cases with apparently normal karyotype. Though representing
a laboratory artifact, the finding of a normal karyotype in low-grade
lymphomas is clinically important, in that it reflects low mitotic
activity of the neoplastic clone, a feature that was associated with a
favorable prognosis in B-CLL40 and in follicle center cell
lymphomas in which the percentage of normal metaphases in lymph-node
samples was associated with a more favorable outcome.20,24
Our finding that patients with normal cytogenetics or with
t(11;14)/BCL1 rearrangement as the only detectable change (group 1)
fared better than patients with additional chromosome changes
represents, to the best of our knowledge, the first demonstration that
MCL may benefit of cytogenetic investigations for a more accurate
assessment of prognosis.
Point 2 is better illustrated in our series by those patients having a
t(11;14) as the sole aberration by CCA, who were shown to carry extra
chromosome 12 material in 26% to 58% of the interphase cells (cases
15.9; 17.13; 18.22; 20.38; 29.33). The possibility that in some
patients with complex karyotype (cases 13.1; 14.6; 26.4), partial
trisomy 12 was not recognized at karyotyping due to the presence of
marker chromosomes, should be considered. It is noteworthy that in
B-CLL, CCA was reported to underestimate the incidence of +12 compared
with interphase cytogenetics, both in cases with normal
karyotypes41 and with complex
rearrangements.42,43 The acquisition of extra chromosome 12 material was detected much less frequently in follicle center cell
lymphoma and in marginal zone B-cell lymphoma in three studies using
comparative genomic hybridization,44-46 suggesting that
this chromosome imbalance may be preferentially associated with
CD5+ B-cell lymphoproliferative disorders. These
considerations have practical implications, because total/partial
trisomy 12 was the only single cytogenetic parameter that was
predictive of an adverse outcome in this series, and point at the
importance of FISH for the refinement of cytogenetic diagnosis in MCL.
Point 3 is illustrated by those cases having cytogenetically undetected
13q14 and 17p13 deletions. Our findings are reassuring with respect to
the specificity of metaphase banding analysis and show that the
sensitivity of CCA in detecting loss of chromosome material is unsatisfactory.
The high incidence of 13q14 deletions (52.3%) that was found in this
series is a relatively new finding, this anomaly having been associated
with 40% of B-CLL studied by molecular
cytogenetics.36,43,47 Interestingly, 13q14 deletion was
found to occur by FISH at a relatively high incidence in atypical CLL
carrying the 11;14 translocation34 and in a recent study on
MCL.48 Because a 8.8% incidence of 13q14 deletion was
found at our Institution in 91 samples of B-NHL excluding MCL and small
lymphocytic lymphoma (data not shown), we suggest that loss of genetic
material involving the 13q14 region may represent an important step in
the transformation of CD5+ B-cell neoplasias.
Whereas the 13q-anomaly carries a favorable prognostic significance in
B-CLL, no statistically significant survival difference was noted in
our patients with and without 13q14 deletion. A trend towards a shorter
survival was observed instead in 13q-patients, partially accounted for
by the presence of additional aberrations in half of the cases. It is
noteworthy that 13q14 deletions are found, albeit at a lower frequency,
in a spectrum of lymphoid neoplasias,49 including multiple
myeloma, in which they have been associated with an inferior
prognosis.50,51
The 26.2% incidence of 17p13 deletion in this series is comparable
with the 18% incidence that was reported by Clodi et al,52 who analyzed by interphase FISH 79 unselected NHL using a 17p13/p53 probe. No correlation was found in this study and in the analysis by
Clodi et al52 between deletion involving this region and survival; hence it is reasonable to assume that p53 gene deletion per
se does not have a major impact on prognosis in NHL. As for the case
with 13q14 deletions, the possibility should be considered that more
cases need to be studied to allow a single cytogenetic parameter to
reach statistical significance on survival analysis, even more so that
a number of chromosome changes was frequently found in association with
each of these anomalies.
This consideration prompted us to define a measure of karyotype
complexity to compare survival among different patient groups. Derived
measures of karyotype complexity, ie, modal chromosome number, number
of translocation breakpoints, and number of marker chromosomes were
shown to have prognostic significance in low-grade NHL and in follicle
center cell lymphomas.20,26 The difference in survival
according to the number of chromosome lesions that was observed in our
study was evident using data obtained by CCA and the observed
difference had an optimal statistical significance using CCA plus FISH
data. This classification clearly depends on the probes that we chose
to test in interphase cells, based on the identification of the most
frequent additional changes by CCA. Other chromosome regions that may
potentially have prognostic significance20,26 were shown to
be deleted or rearranged in a fraction of MCL,38 the most
frequent being 6q15-21, 6q25, 1p21-32, and 1q21-23. Attention was
devoted in a recent study on a cycline-dependent kinase (CDK)
inhibitor, referred to as p16INK4a and located on
chromosome 9p21, the deletion of which was shown to be associated with
a high proliferation index.53 Interestingly, the gene
encoding for a closely related CDK inhibitor, p18INK4c, was
mapped to 1p31-35,54 in a chromosome segment that was deleted in two of our cases. In general, it is reasonable to predict that, as more cases will be studied, new recurring chromosome breaks
will be recognized that will allow for the definition of a wider panel
of FISH probes, possibly resulting in the identification of other
clinically important genomic imbalances.
 |
FOOTNOTES |
Submitted August 3, 1998; accepted October 12, 1998.
Supported by BMH-1 EU CA: CT 94-1703, and by C.N.R., ACRO project and
M.U.R.S.T, fondi 40% and 60%.
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 correspondence to Antonio Cuneo, MD, Institute of Haematology,
University of Ferrara, Via Savonarola, 9, 44100 Ferrara, Italy; e-mail:
sse{at}dns.unife.it.
 |
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