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Prepublished online as a Blood First Edition Paper on January 2, 2003; DOI 10.1182/blood-2002-11-3456.
NEOPLASIA
From the Centro Nacional de Investigaciones
Oncológicas (CNIO), Molecular Pathology Program, Madrid,
Spain; Department of Genetics and Pathology, Hospital
Virgen de la Salud, Toledo, Spain; Department of
Hematology and Medical Oncology, Hospital Clínico, University
of Valencia, Valencia, Spain; Department of Hematology,
Hospital Clínico, Salamanca, Spain; Laboratory of
Citología Hematológica, Department of Pathology, Hospital
del Mar, Barcelona, Spain; Department of Pathology,
Hospital Clinic, Barcelona, Spain; and Department of
Pathology, Hospital Gregorio Marañón, Madrid,
Spain.
This study explores whether the presence of somatic mutations or a
biased use of IgVH genes were
associated with the clinical features in a series of 96 patients with
mantle cell lymphoma (MCL). The cases were studied by seminested
polymerase chain reaction using primers from the FR1 and JH
regions. There was an unexpectedly high frequency of somatic mutations,
with 29 of 103 sequences showing more than 2% of mutations. Biased usage of specific VH segments was also found;
the most widely used genes in this series were
VH3-21 (10 cases),
VH3-23 (9 cases),
VH4-34 (11 cases), and
VH4-59 (9 cases).
VH mutation frequency, taking into account
different thresholds, did not distinguish different overall survival
probabilities. Nevertheless, a more frequent use of
VH3-21 or VH4-59 (8 of
18) was observed in the group of long-term survivors (18 cases > 5 years; P < .01). None of these long-term survivors
presented the VH3-23 gene rearrangement. As in
other lymphoproliferative disorders, the expression of CD38 or p53 or
both was associated with a poorer survival probability. This nonrandom
usage of IgVH segments suggests that specific
antigens may play a pathogenically relevant role in the genesis or
progression of subsets of MCL cases and may help in distinguishing a
significant group of MCL long-term survivors.
(Blood. 2003;101:4042-4046) The presence of somatically acquired
IgVH mutations is considered a consequence of
the exposure of B cells to the microenvironment of the germinal center.
Thus, it has been exploited as a distinctive feature of benign B cells
and malignant lymphomas. The analysis of IgVH
mutations in B-cell lymphomas has revealed an unsuspected heterogeneity
in some small B-cell lymphomas, such as B-chronic lymphocytic leukemia
(B-CLL)1,2 and splenic marginal zone lymphoma
(SMZL).3,4 In both conditions, approximately half of the
cases bear IgVH mutations in at least 2% of the
sequence. This relationship is associated with lower clinical
aggressiveness and extended survival. Additionally, a biased use of
VH genes has been demonstrated in B-CLL and
SMZL, with an increase in the frequency of
VH1-69 and VH 1-2,
respectively, thus suggesting that these lymphoproliferative process
types could be related to specific subsets of B lymphocytes, primed for
their growth by autoantigens or superantigens.1,5
Mantle cell lymphoma (MCL) is a B-cell lymphoma characterized by the
translocation t(11;14)(q13;q32) that results in overexpression of
cyclin D1 protein. MCL represents 3% to 10% of non-Hodgkin lymphoma
(NHL) and has a median survival of 3 to 5 years. Despite this
relatively short survival, subsets of patients with MCL show a more
favorable clinical course with a relatively long period of stable
disease. Additionally, MCL cases are cytologically heterogeneous; a
subset of aggressive MCL cases has been identified that has a blastoid
cytology and is associated with frequent inactivation of p53 and p16
genes.6-8
Although it has long been assumed that MCL cells bear unmutated
IgVH genes,9-11 recent investigations have
revealed that somatic mutations in the immunoglobulin genes are present
in a significant fraction of MCL cases.12 Here we have
analyzed a series of 96 MCL cases, a number large enough to reveal even
slight but significant associations between the presence of somatic
mutation, the use of specific IgVH genes, and the
morphologic or clinical variability of MCL cases.
Patients and tissue samples
Patient medical records were reviewed to determine age, sex,
localization, and stage of disease at diagnosis, splenomegaly at
diagnosis, International Prognostic Index (IPI), and disease course.
Cases were considered as primary gastrointestinal or Waldeyer ring
types when the disease was restricted to these organs. Approval was
obtained from the institutional review board of Hospital Universitario La Paz for this study. When necessary, informed consent was provided according to the Declaration of Helsinki.
Immunohistochemistry
IgVH study Rearranged IgVH genes were amplified using a seminested polymerase chain reaction (PCR) method, as described previously.13 In the first round of PCR, a mixture of 6 framework 1 (FR1) VH family-specific primers and 2 consensus primers for the JH gene were used. The second round of PCR was performed in 6 separate reactions with 1 of the 6 VH FR1 primers and JH internal primers.Briefly, 200 ng DNA was amplified in a volume of 50 µL with 1 × PCR buffer, 200 µM dNTPs (deoxyribonucleoside triphosphate), 2.5 mM MgCl2, 250 nM each primer, and 1 U AmpliTaq gold. In the second round of amplification, the same concentrations of reagent were used, except for MgCl2, which was 1.5 mM. Then, 1 µL of the first-round PCR product was added to the seminested reaction as a template. The PCR conditions have been described previously.3 Direct sequencing was performed on both strands using the same primers as in the amplification. The direct sequencing procedure was performed using an ABI PRISM 310 or 3700 Genetic Analyzer (Applied Biosystems, Weiterstadt, Germany), following the manufacturer's procedure. Mutations were identified by comparison with the germline sequence (Ig BLAST at http://www.ncbi.nlm.nih.gov/igblast and V BASE at http://www.mrc-cpe.cam.ac.uk/vbase-ok sequence directories). To determine whether the number of replacement (R) and silent (S) amino acid substitutions identified were indicative of antigen selection, the Chang and Casali method was used.14 Statistical analysis Survival analyses were performed using the Kaplan-Meier method. Statistical significance of associations between individual variables and overall survival was determined using the log-rank test. The Cox univariate proportional hazard analysis was also performed independently for each variable to estimate relative risk [Exp (B)], and the associated 2 value for assessing significance.
P < .05 was considered significant. Survival probability
was analyzed using a Cox multivariate analysis, including all the
variables with a P < .1. All statistical analyses were carried out using SPSS for Windows (Chicago, IL).
Clinical features Ninety-six patients meeting the criteria for MCL diagnosis were enrolled, 72 men and 24 women. The median age was 66 years (range, 32-86 years). Eighty-seven of them were at stages III or IV at diagnosis; the IPI group distribution was 20 high-risk (4 or 5), patients, 54 intermediate risk (2 or 3), and 20 low-risk (0 or 1) cases. Twenty-six patients presented splenomegaly at the time of diagnosis and only 5 of them were considered as purely splenic forms. Six cases were considered to be the primary gastrointestinal form of MCL, another 6 as the primary Waldeyer ring form, and an additional case presented initial involvement of both territories. Infiltration of the PB or BM (or both) was observed in 51 cases. The median follow-up period for the entire series was 25 months (range, 0-133 months).VH gene usage in MCL In this series of 96 MCL cases, we have amplified and sequenced 103 clonal IgVH rearrangements. There were 7 cases with 2 different rearrangements. Among the 103 clonal VH gene sequences, 100 were potentially functional and 3 were rendered nonfunctional by out-of-frame rearrangement (stop codon). In 4 of 7 cases, 2 apparently productive VH gene rearrangements were obtained, which probably represents a lack of allelic exclusion, similar to that described in B-CLL.15The similarity of the VH genes to the closest
germline gene segment is shown in Table
1. The most frequent
VH family was VH3 (46%
of the sequences), followed by VH4 (29%), VH1 (20%), VH5 (3%),
and VH2 (2%). The frequencies of the used VH families differ from those usually present in
peripheral and lymph node lymphocytes in healthy individuals, mainly as
a consequence of the higher frequency of VH4
family genes observed here.
The 103 rearranged VH gene sequences used by these 96 cases have a striking bias toward using specific genes, such as VH3-21 (11.8%), VH4-34 (10.8%), VH3-23 (8.8%), VH4-59 (8.8%), and VH4-39 (7.8%), by comparison with the relative frequencies in peripheral blood lymphocytes (PBLs). There was no difference in the usage of VH families or segments among the cases analyzed by tissue biopsy or PB. Mutational analysis The frequency of mutations was higher than previously described, with around one fourth (29 of 103) of IgVH rearranged genes showing more than 2% of mutations. There was a group of 13 rearranged IgVH genes with a high mutational index (defined as > 5% of mutations). The range of percentage of mutations was from 0.42% to 16%, with a mean of 1.89% (Table 2).
There was no significant relationship between the mutational index and
the VH family, although studying the
relationship between the mutational index and the use of specific
VH genes reveals statistically significant
differences (P < .001). Thus, all
VH3-21 (12 of 12) sequences were unmutated
(> 98% homology) and had on average 0.30 mutations, whereas 5 of 9 VH3-23 sequences and 3 of 3 VH3-48 rearrangements showed mutations, with
respective mean numbers of mutations of 3.28 and 5.82 (Table
3).
The mutational index was higher (> 5%) for cases whose clinical staging revealed BM or PB infiltration. Additionally, cases with extranodal involvement at diagnosis were shown to have a low mutational load (< 5%). Cases considered as primary splenic forms of MCL (5 cases) carried a high mutational index (3 of 5 cases > 5%; P < .05). Mutational index was independent of architectural pattern (diffuse/nodular/mantle zone) and cytology (classic/blastoid). A specific search was performed to examine the hypothetical association of high somatic mutation with the presence of cyclin D1+ tumor cells in the germinal center microenvironment. These intragerminal center cyclin D1+ cells were observed in 20 of 56 cases, although there was no significant relationship with the mutational index (Table 2). VH3-21 cases.
All 12 VH3-21 sequences had a lower mutational
index (mean, 0.30) than the remaining MCL cases. Ten cases with
VH3-21 as the only rearrangement (mean
mutational index, 0.18) also had a relatively low frequency of BM and
PB infiltration. These VH3-21 cases exhibited a
better survival probability, 4 of 10 remaining alive 5 years from
diagnosis (Figure 1).
VH3-23 cases. Mutation frequency was distinctly higher in the 9 cases with VH3-23 (mean mutational index, 3.28; 5 cases > 2% mutations). Patients in this group were characterized by a more aggressive clinical course, all of them having died within 5 years of the diagnosis (Figure 1). A relatively high frequency of splenomegaly (5 of 9) at diagnosis was observed in this group. VH4-59 cases. A low mutation frequency (mean, 1.53; 1 case > 2% mutations), combined with a relatively high frequency of splenomegaly and PB/BM infiltration at diagnosis, was observed in this group. Cases using VH4-59 show a trend for a better survival probability (Figure 1), with 4 of 9 alive at 5 years after diagnosis. Antigen selection The distribution of replacement (R) and silent (S) mutations was analyzed by considering all possible mutations, as described by Chang and Casali14 in 26 mutated cases (> 2% of mutations). One of the 26 cases presented a double VH rearrangement, both mutated, and it was only considered the in-frame sequence. No statistically significant evidence for antigen selection was observed in 16 sequences. In the other 10 cases, there was evidence for negative selection, whereby fewer replacement mutations than expected were seen in the FR regions, indicating pressure to maintain the germinal configuration.Other immunohistochemical and morphologic results Other markers analyzed in this series were CD27 (14 of 55 positive), CD5 (58 of 76 positive), CD38 (50 of 67 positive), p53 (13 of 71 positive), IgD (54 of 65 positive), and Ki67 (42 low, 27 high). Blastoid cytology was present in 14 of 86 cases.Overall survival predictors The capacity of all these variables to predict overall survival probability was evaluated (Table 4). VH mutation frequency, taking into account the different thresholds, did not distinguish different overall survival probabilities among the patients.
Parameters found to be significant predictors of survival probability were the IPI, splenic involvement at diagnosis, tetraploidy, proliferation index (Ki67), and the expression of CD38 or p53. A trend was also observed for higher survival probability to be associated with the use of VH3-21 (P = .061; Exp (B) = 0.290) and a nonsignificant tendency with VH4-59, whereas a trend was observed for an unfavorable prognosis of the use of VH3-23 (P = .066; Exp (B) = 2.47). Combining cases using VH3-21 and VH4-59 in a single group, the survival analysis revealed significantly longer survival for this group (Figure 1). The series included a small group (18 cases) of long-term survivors (> 5 years). A review of the characteristics of these patients revealed significant differences in VH gene usage. Almost half (8 of 18) showed expression of either VH3-21 or VH4-59, compared with 14.9% in the group with less than 5-year survival (P < .01). None of these long-term survivors presented the VH3-23 gene rearrangement. Long-term survivors also have a lower frequency of CD38 expression (45.5% versus 80.8%; P < .05) and CD38 or p53 expression (45.5% versus 84.3%; P < .05). Finally a Cox multivariate analysis showed that both the use of
VH3-21 or VH4-59 and the
expression of CD38 or p53 predicted the overall survival probability
independently of the IPI (Table 5). The
patients were ranked according to their score, estimated by Cox
multivariate analysis, and divided into two groups of identical size
(the bottom 50% and the top 50%) and into quartiles (Q). The bottom
50% and the top 50% corresponded to low and high estimated risk
groups, respectively; Q1, Q2, Q3 and Q4 included low, intermediate-low, intermediate-high and high estimated risk cases, respectively. Their
survival probability was then estimated by the Kaplan-Meier method
(Figure 1).
This study analyzes the incidence and distribution of somatic mutations in VH genes in a series of 96 cases diagnosed as MCL. To guarantee the homogeneity of the series, we used restrictive inclusion criteria. The results show that 27% of the sequences presented less than 98% homology with the germinal sequence. Mutation frequency appears not be distributed at random, but is related with the use of specific IgVH genes and, to a lesser but still significant extent, with particular anatomic localizations. The percentage of mutated cases in this series is slightly higher than that previously reported (20% in the series of 51 cases studied by Thorselius and coworkers),12 although this may depend on the smaller size of the latter series. VH3-21 usage in MCL appears to be associated with a low mutational index and a relatively favorable clinical course. Most of these cases seem to have a disease that is mainly restricted to lymph nodes. This contrasts with the observations performed in B-CLL, where the use of VH3-21 is associated with a high mutational index and a more aggressive clinical course.2 This contradiction seems to support the interpretation that mutation frequency is not dependent on the usage of a specific IgVH gene, but is perhaps related to some unknown antigens that are of probable significance in the pathogenesis of this MCL subset. The most favorable outcome of the VH3-21 cases is shared by the VH4-59 cases, quite the opposite of what is observed in VH3-23 cases. Thus, VH3-23 cases, with their higher mutational index, show a trend toward more aggressive behavior. Frequency of BM or leukemic infiltration was significantly higher in these groups of cases harboring the VH3-23 gene. Other prognostic factors found here are tetraploidy and the association of p53 and CD38. Previous observations have already demonstrated that karyotypic complexity has a strong impact on prognosis in MCL,16,17 and the presence of tetraploidy here is probably associated with the blastoid cytology, which usually pursues a more aggressive course.18 A paradoxical observation in this series is that blastoid cytology is not related with more aggressive behavior, whereas p53 expression, increased growth fraction, and tetraploidy, all of which are usually associated with blastoid cytology, are associated with this poorer outcome. This implies that a reconsideration of the diagnostic criteria for the blastoid variant of MCL could provide a more accurate clinical meaning of this diagnosis. CD38 expression appears also to predict shorter survival in this series, mainly when analyzed jointly with p53, thereby mimicking the findings in B-CLL.19-21 The data obtained in this study also allow recognition of a group of MCL patients with relatively long-term survival (> 5 years), which seems to depend on an association between the use of specific VH genes and the lack of adverse prognostic markers. Despite the adverse outcome for MCL patients, repeated observations indicate the existence of a distinct group of cases that seem to display a relatively long period of stable disease. Molecular heterogeneity of MCL, taking into greater account the usage of specific genes than the frequency of mutations, goes some way to explain this clinical variability. This nonrandom usage of IgVH segments suggests that specific antigens may play a pathogenically relevant role in the genesis or progression of subsets of MCL cases.
We thank Dr M. Pollán for her valuable help with the statistical analysis, and Drs P. Domínguez, M. Medina, F. Bosch, E. Flores, M. A. Martínez, B. Espinet, M. J. Terol, A. Ferrández, and A. Teruel from the Hospitals of Alcorcón (Madrid), Virgen de la Merced (Osuna), Hospital Clinic of Barcelona, Hospital General Universitario Gregorio Marañón (Madrid), Hospital 12 de Octubre (Madrid), Hospital del Mar (Barcelona), and Hospital Clínico Universitario (Valencia), Spain, for kindly providing the clinical data for the cases included in this series.
Submitted November 15, 2002; accepted December 23, 2002.
Prepublished online as Blood First Edition Paper, January 2, 2003; DOI 10.1182/blood-2002-11-3456.
Supported by grants from the Comunidad Autónoma de Madrid (CAM 08.1/0011/2001.1), the Ministerio de Sanidad y Consumo (FIS 01-0035), and the Comunidad Autónoma de Castilla-La Mancha (02031-00), Spain. F.I.C. is supported by a grant from the Madrid City Council and the CNIO.
F.I.C. and P.A. contributed equally to this work.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Miguel A. Piris, Molecular Pathology Program, Centro Nacional de Investigaciones Oncológicas, C/ Melchor Fernández Almagro 3, E-28029 Madrid, Spain; e-mail: mapiris{at}cnio.es.
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Top
Abstract
Introduction
)/IgM+ B cells.
J Clin Invest.
1997;99:2488-2501