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Blood, Vol. 94 No. 5 (September 1), 1999:
pp. 1738-1746
VH Gene Sequences From Primary Central Nervous System
Lymphomas Indicate Derivation From Highly Mutated Germinal Center B
Cells With Ongoing Mutational Activity
By
Andrew R. Thompsett,
David W. Ellison,
Freda K. Stevenson, and
Delin Zhu
From the Molecular Immunology Group, Tenovus Research Laboratory and
the Department of Pathology (Neuropathology), Southampton University
Hospitals Trust, Southampton, UK.
 |
ABSTRACT |
Primary central nervous system lymphoma (PCNSL) represents 1% to
3% intracranial tumors. Most PCNSL are located in the brain, and 75%
are large B-cell lymphomas. The largest subgroup of these tumors
contains cells that resemble centroblasts and has been labelled diffuse
centroblastic (polymorphous) lymphoma. To investigate the cell of
origin and the clonal history of these tumors, we have analyzed
VH gene of 5 cases of PCNSL, all confirmed by histological studies to be Epstein-Barr virus (EBV)-negative,
high-grade diffuse B-cell lymphomas. The V4-34 gene of the
VH4 family was used in 4 of 5 cases. All VH
genes were found to have accumulated very high levels of somatic
mutation (14% to 25%). In 3 of 5 cases, intraclonal nucleotide
heterogeneity, including codon deletion in some clones in 1 case, was
observed, indicating that the VH genes were still under the
influence of the somatic hypermutation mechanism. Analysis of the
distribution of silent and replacement mutations showed evidence for
preservation of immunoglobulin structure in all cases. These results
suggest that, although there is no evidence for germinal center
formation in the brain tissue, PCNSL is derived from a B cell with
features associated with location in a germinal center environment.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
PRIMARY CENTRAL NERVOUS system lymphoma
(PCNSL) is an uncommon neoplasm, representing 1% to 2% of lymphomas
and 1% to 3% of intracranial tumors.1,2 While most
examples of PCNSL are sporadic, some are associated with congenital or
acquired immunodeficiency. An increasing incidence of PCNSL can partly be attributed to a growing population of immunocompromised patients in
which PCNSL is mainly associated with the acquired immunodeficiency syndrome, organ transplantation, and chemotherapy.
PCNSL has been associated with a poor prognosis, which is worse than
that for similar non-Hodgkin's lymphomas outside the CNS.3
However, recent trials of radiotherapy with various chemotherapeutic
regimens have shown an improvement in survival.4,5 Most
PCNSLs are located in the brain, and about 75% are large B-cell
lymphomas (REAL classification). The largest subgroup
of these large cell lymphomas contains cells that resemble
centroblasts6 and has been labeled diffuse centroblastic
(polymorphous) lymphoma (Kiel classification). Other B-cell PCNSLs are
low-grade lymphocytic, lymphoplasmacytic, and plasmacytic lymphomas.
T-cell PCNSLs are very rare, but large and small cell examples have
been reported.1
Generation of functional antigen receptors by somatic recombination of
variable, diversity, and joining segments is a unique feature of B
cells and T cells. In a normal immune response, B lymphocytes
stimulated by antigen can undergo somatic hypermutation in their
immunoglobulin (Ig) variable region genes in a germinal center
microenvironment, thus generating a more diverse repertoire of
antibodies. B cells with high affinity for antigen are selectively rescued from apoptosis to differentiate into either circulating memory
cells or antibody-producing plasma cells.7,8 From the
developmental point of view, B-cell tumors can be regarded as B cells
arrested at a certain differentiation stage when neoplastic transformation took place. Analysis of Ig V region genes has provided invaluable information on the status of tumors in B-cell
differentiation and has added another dimension to classification of
B-cell tumors at the molecular level.9,10 In the case of
follicular center lymphoma (FCL), V genes are often somatically mutated
and in some cases significant accumulation of replacement mutations is
found in the complementarity-determining regions (CDRs), suggesting a
selective role for antigenic stimulation. Furthermore, intraclonal nucleic acid sequence variation appears to be a common feature of FCL,
an indication that tumor cells are still under the influence of a
mutation mechanism.11-14 Recent studies have also shown
that VH genes in primary diffuse large cell lymphomas
(DLCL) are somatically mutated,15-18 with a significant
level of intraclonal heterogeneity, again indicating ongoing somatic
mutation.16 Interestingly, the heterogeneity is reduced
after successful chemotherapy, possibly due to selective pressure on
the clone.16 There have been few studies of Ig V genes on
PCNSL. Southern blotting and polymerase chain reaction (PCR)
amplification of the VH CDR3 sequences have demonstrated Ig
V-gene rearrangement in most cases, confirming the B-cell nature of
PCNSL.19-21 To gain insight into the nature of the Ig V
genes in PCNSL, we cloned and sequenced the complete VH
genes of 5 cases of PCNSL. We have found frequent usage of the V4-34
gene. We have also found that the VH genes are extensively mutated and show intraclonal heterogeneity in some cases, reminiscent of alterations influenced by the germinal center environment.
| |
MATERIALS AND METHODS |
Immunohistochemistry and in situ hybridization.
Tumor biopsies were examined by standard histological techniques,
including immunohistochemistry as previously described.22 A
range of antibodies (DAKO, Glostrup, Denmark) to immunoglobulins, and
B-cell and T-cell-specific antigens was used at the following concentrations: IgM 1:500; IgG 1:1,000; IgA 1:500; Kappa 1:500; lambda
1:500; CD20 1:400; CD79a 1:250; CD3 1:50; CD45RO 1:1,000. Sections (5 µm) were also probed for Epstein-Barr virus (EBV)-encoded RNA (EBER)
transcripts using an in situ hybridization kit (Novocastra, Newcastle,
UK) with appropriate positive and negative controls.
Preparation of cDNA.
Frozen tumour tissue ( 0.1 g) was cut into small pieces and ground
into fine powder in liquid nitrogen in a mortar. The powder was
transferred to a microcentrifuge tube, and total RNA was isolated using
RNAzol according to the supplier's instructions (Cinna Biotecxlabs Inc, Houston, TX). First-strand cDNA was synthesized from 5 µg of
total RNA in a final volume of 33 µL using a cDNA synthesis kit and
oligo(dT) primer (Pharmacia, Uppsala, Sweden).
Amplification, cloning, and sequencing of VH genes.
For amplification of VH genes from cDNA, 1 to 5 µL of
cDNA was used as template for PCR using a mixture of oligonucleotide primers specific for each of the leader sequences of VH 1-6 families (Table 1), together with a mixture
of primers complementary to the sequences of the germ line
JH genes.23 In some cases, a Cµ constant
region primer was also used. PCR was performed in a final volume of 50 µL containing 1 to 5 µL of cDNA, 20 pmol of each primer, 250 mmol/L
of dNTPs, 2.5 U of Taq DNA polymerase with the reaction
buffer supplied by the manufacturer (QIAgen, Hilden, Germany). PCR
consisted of an initial denaturation step of 5 minutes at 94°C,
followed by 35 cycles of 94°C for 60 seconds, 65°C for 60 seconds, and 72°C for 60 seconds, with a final extension step of 10 minutes at 72°C. PCR products (400 bp) were separated by agarose
gel electrophoresis, purified using the GeneClean kit (Bio 101 Inc,
Vista, CA), and cloned into the pGEM-T vector (Promega, Madison, WI).
Randomly picked bacterial clones were sequenced on an ABI 377 automatic
sequencer (Perkin-Elmer, Foster City, CA).
Analysis of VH gene usage and mutation pattern.
Tumor-related VH genes were identified as predominant
repeated or similar sequences with clonally related CDR3.23
Sequence alignment analysis was to the Entrez database (National Center for Biotechnology Information, Bethesda, MD) and to the VBase, which
contains all known human germ line immunoglobulin V region genes24 using MacVector sequence analysis software (Oxford
Molecular, Oxford, UK). The germ line genes with highest homology to
the tumor-derived sequences are considered as the germ line gene
donors. Statistical analysis of mutation distribution was performed
according to Chang and Casali.25 In this method, each V
gene is analyzed codon by codon for significance of deviation from the
germ line sequence. A modified binomial distribution model is then
applied to calculate whether the probability (p) of excess (in
CDR) or scarcity (in framework region [FR]) of R
mutations resulted from chance alone.
| |
RESULTS |
Clinical and histological data.
All 5 patients, of whom 4 were female, presented with CNS symptoms and
signs. Their ages ranged from 50 to 71 years (median, 60 years). None
had detectable lymphadenopathy, and none was immunocompromised. Neuroimaging showed mass lesions in the cerebrum (3 patients) or
cerebellum (2 patients), which were thought to be neoplastic in nature.
Biopsy of all tumors was undertaken at the Wessex Neurological Centre
where concurrent radiological investigations failed to show tumor
outside the CNS. In all cases, histological examination showed the
typical architectural and cytological features of a high-grade
(polymorphous) B-cell PCNSL (Fig 1),
including the characteristic perivascular arrangement of neoplastic
cells and invasion of adjacent brain tissue to form intraparenchymal
masses.
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| Fig 1.
PCNSL histology. (A) Brain at the periphery of a PCNSL
characteristically shows accumulation of neoplastic cells in the
perivascular spaces (periodic acid Schiff; original magnification
[OM] × 250). (B) Invasion of surrounding brain by neoplastic cells
occurs from the perivascular space (periodic acid Schiff; OM × 500).
(C) A sheet of neoplastic lymphoid cells characterizes this
intraparenchymal large cell PCNSL. Moderate nuclear pleomorphism, a
variable number of nucleoli per cell, and mitotic figures are evident
(hematoxylin and eosin; OM × 500). (D) All tumors in this study were
positive for CD20 (L-26 antibody, immunoperoxidase; OM × 500).
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Immunohistochemistry confirmed a B-cell immunophenotype for the
neoplastic cells in each case (Table 2).
All tumors expressed CD20 (Fig 1) and CD79a. Antibodies to CD3 and
CD45RO labeled moderate numbers of reactive T lymphocytes among the
neoplastic cells. Immunohistochemistry with antibodies to IgM, IgG,
IgA, and kappa and lambda light chains was feasible in 3 of 5 cases.
IgM and kappa light chains were detected in neoplastic cells in all 3 cases. In 1 tumor, sparse IgG-positive cells were detected in addition
to more widespread IgM. No IgA was detected. All 5 tumors were
EBER-negative by in situ hybridization.
Usage of VH, D, and JH genes in the tumors.
Preparations of cDNA from all 5 patients were amplified, cloned, and
sequenced. In all cases, predominant repeated or similar clones with
identical CDR3 sequences were obtained, consistent with tumor
derivation (Table 3). The usage of
VH, D, and JH genes and the homology to the
corresponding germ line genes are summarized in Table 3. Sequence
analysis indicates that the V4-34 gene of the VH4 family
was used in 4 of 5 patients, and in the remaining case, the
VH gene was derived from V3-23, a member of the
VH3 family. Assignment of D gene segments was based on the
homology between CDR3 sequences and the germ line D genes. According to the rule proposed by Corbett et al26 that at least 10 consecutive nucleotides of identity are required to assign a D segment,
D gene can only be identified with confidence in patient 4. However, shorter D segments or D segments with nucleotide substitutions could
have been used in the other cases and are also shown in Table
3. There was no apparent bias in JH gene
usage. JH6 gene was used in cases 1 and 5, JH3
in case 2, and JH4 in case 4. The JH gene in
case 3 was extensively truncated at the 5' end, which could be
derived from either JH1 or JH5.
Somatic hypermutations in tumor-derived VH genes.
The nucleotide sequences of the tumor VH genes and the
deduced amino acid sequences are shown in
Figs
2 and 3. A large number of nucleotide
substitutions was found in all tumor VH genes, ranging from
41 to 73 nucleotides (14% to 25% of the VH genes). In
addition to single nucleotide change, double and triple substitution
also frequently occurred, mostly within the same codon. No nucleotide insertion was observed, but triple in-frame as well as single nucleotide deletion was seen in a number of clones in case 1 (see below). Among the V4-34-derived sequences, common nucleotide
substitutions leading to both silent and replacement mutations were
seen in several codons, such as Gln5, Val71, and Ser35 (Fig 3). To see if there was significant clustering of replacement (R) mutations in the
CDRs and silent mutations in the FRs, the distribution of somatic
mutations was analyzed by the method of Chang and Casali25 (Table 4). The analysis shows that the
number of R mutations in FRs was significantly lower in all cases
(P < .05), probably as a result of selection against R
mutations within the FRs to preserve the structures of expressed
immunoglobulins. In patient 2, the number of R mutations in CDRs was
significantly higher than would be expected to arise solely by chance
(P < .05), whereas in the other cases, the number of
replacement mutations in the CDRs was not significantly higher than
expected (P > .05).
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| Fig 2.
Nucleotide and
deduced amino acid sequences of VH genes derived from
PCNSL. Comparisons were made with the most homologous germ line
VH genes. Dashes represent identity with the representative
germ line sequence. Replacement amino acids are starred. Blank space
indicates nucleotide deletion. The binding sites for JH
primers are shown in italics. For patients 1 and 4, full JH
sequences are shown for the clones obtained by PCR using the
VH leader and the Cµ primers. Clones with nucleotide
deletions in case 1 are underlined. The VH gene sequences
have been deposited to the EMBL database with
following accession numbers: patient 1, AJ235649-AJ235661; patient 2, AJ235662; patient 3, AJ235663; patient 4, AJ235664-AJ23566; patient 5, AJ235671-AJ235678.
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| Fig 3.
Deduced amino acid sequences of VH regions of
PCNSL. Comparisons were made with the most homologous germ line
VH genes. Amino acid numbering is according to Kabat et
al.46 Dashes represent identity with the representative
germ line sequence. Uppercase, replacement mutation; lowercase, silent
mutation.
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Intraclonal nucleotide sequence variation.
In 3 cases (1, 4, and 5), intraclonal nucleotide variation was observed
in VH genes (Fig 3). This sequence heterogeneity is considered mostly as the result of ongoing somatic mutation rather than
being introduced in PCR amplification, as the levels of variation (>1
in 700 bp) were much higher than the PCR error
frequency (1 in 5,000 bp in our laboratory) and
several identical base changes were seen in different clones. This is
supported also by the fact that no heterogeneity was observed in cases
2 and 3 with similar numbers of clones sequenced. The level of
nucleotide variation in the 3 cases differs and the variations appeared
to be distributed randomly. Most nucleotide variations were single base
substitutions, resulting in both silent and replacement mutations.
However, deletion of in-frame triple nucleotides, ie, an entire codon,
in 3 different positions in the CDR2 was found in a number of clones in
patient 1. Single nucleotide deletion was also found in 2 clones in
this case, 1 in the FR2 and 1 in the FR3, leading to aberrant
sequences. No nucleotide insertions were observed.
| |
DISCUSSION |
PCNSL is a rare tumor with increasing incidence during the past decade,
both in immunocompromised and in general populations.1 PCNSL shows morphological and immunohistochemical features similar to
those of malignant lymphomas arising in sites outside the CNS. The
B-cell nature of most of these tumors has not only been demonstrated by
immunohistochemistry, but by Southern blotting and PCR amplification of
the short VH CDR3 sequences.19-21 In this small
study of full-length VH gene sequences, VH gene
usage appeared to be restricted as the V4-34 gene was used in 4 of 5 cases. The V4-34 gene is used in 5% of healthy
adults27,28 and appears to be overexpressed in some
autoimmune diseases and B-cell tumors. The V4-34 gene has been shown to
be mandatory for encoding the IgM proteins of cold agglutinin
disease.29,30 In this case, the red blood
cell I/i antigens appear to bind to the FR1 of the Ig. This binding outside the CDRs is indication of a B-cell superantigen. Recently, Hsu
and Levy15 reported that in DLCL there was a preferential usage of genes from the VH4 family, especially the V4-34
gene (11 of 17 cases, 65%), although a recent study31
using the V4-34 gene product-specific antibody, 9G4, showed that only
30% of DLCL expressed the V4-34 gene; and the sequence analysis by
Küppers et al17 and a study of 11 cases of DLCL in
this laboratory did not show bias toward V4-34 gene (C. Ottensmeier,
personal communication, September 1998).
VH4 family genes, but not V4-34, also appear to be
preferentially used in the B cells from cerebrospinal fluid in multiple
sclerosis.32,33 If such bias were to be confirmed in PCNSL,
it might suggest a role for superantigen drive in lymphoma development.
It is interesting that certain infections, including EBV,
cytomegalovirus, and mycoplasma pneumoniae, cause a selective increase
in serum levels of V4-34 encoded Ig. Although the cerebral tumors
described are EBV-genome negative, this intriguing association may
indicate a potential influence of pathogens on B cells expressing V4-34
encoded Ig.
The VH genes of all 5 cases were very heavily mutated. In
fact, the somatic mutation frequency in these cases (mean ± standard deviation [SD]% = 18.4 ± 3.7%) is higher than in all
of the other B-cell malignancies studied so far (summarized by Klein et
al10). In DLCL, which involves cells morphologically and
phenotypically similar to PCNSL, a mean mutation frequency of 11%
(range, 4% to 22%) was reported.17 Despite high levels of
somatic mutation in PCNSL, there is good evidence for selection against
R mutations in the FRs, suggesting that functional expression of the Ig
receptor may be advantageous for tumor growth. Some shared nucleotide
substitutions leading to silent as well as replacement mutations were
seen among the V4-34 encoded sequences. The intrinsic mutational
"hot spots" are likely to be responsible for these common
mutations, as the same changes in the V4-34 gene have been observed in
different studies,15,34 and biased nucleotide substitution
is a general feature of both human35 and murine IgV
genes.36
Intraclonal heterogeneity was observed in 3 cases, suggesting that the
tumor cells retained the capacity to undergo further somatic
hypermutation. In case 1, which was the most mutated, deletion of
in-frame triple nucleotides occurred in 2 different positions in the
CDR2; therefore the gene could still be expressed. However, in 2 clones, the reading-frame was disrupted by single nucleotide deletion
and therefore no Ig could be produced. Possibly, these sequences were
derived from the cells that contained deleterious mutations and were
due to die, but had not yet been eliminated from the tumor population.
Nucleotide deletion and insertion have also been reported in other
B-cell tumors.37-39 However, insertional or deletional
events are not unique to tumor cells because there is strong evidence
that nucleotide insertion and deletion are frequently introduced in the
somatic hypermutation process, and in-frame insertion and deletion have
been found in normal B cells.40,41
The pattern of somatic mutation and intraclonal variation indicates
that the cell of origin of PCNSL has been exposed to the mutational
mechanism, both before and after neoplastic transformation. This
pattern is characteristic of tumors of germinal center origin, such as
FCL, and is also seen in Burkitt's lymphoma, mucosa-associated lymphoid tissue (MALT) lymphoma and
DLCL.9,10 Stimulation of somatic mutation is generally
considered to require a GC environment where activated T cells and
cytokines are present.7,8 Cross-linking of surface Ig also
may increase the rate of somatic mutation, possibly reflecting a role
for antigen.42
For PCNSL, there is no evidence for GC structure in the brain. However,
PCNSL cells do express BCL-6 protein.43 PCNSLs are mainly
located in the cerebral parenchyma and can infiltrate the pial or
ependymal surfaces to spread along the edge of CSF
pathways, with no particular anatomical location. One possibility is
that the somatic mutation is occurring independently of GC structure. Support for some GC-independent mutational activity comes from mice
deficient in lymphotoxin- 44 and Lyn
kinase.45 Although these mice cannot form GCs, they are
able to accumulate somatic mutations in V genes. However, levels are
low and would not be expected to reach the very high levels found in
the B cells that give rise to PCNSL.
An alternative possibility is that the B cells of PCNSL have undergone
somatic mutation and neoplastic transformation in a draining cervical
lymph node. These events could have occurred after antigenic
stimulation, perhaps due to infection. However, the neoplastic cells
have then to leave the lymph node and enter the cerebral parenchyma
where they apparently remain. The puzzle is that cervical lymph nodes
are not obviously involved at presentation. Availability of
VH CDR3 sequence tags should now allow an approach to these
questions by probing of blood and bone marrow of patients to track
possible migration of tumor cells from the brain.
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FOOTNOTES |
Submitted December 14, 1998; accepted April 23, 1999.
Supported by Tenovus and the Cancer Research Campaign, UK.
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 Delin Zhu, PhD, Molecular Immunology Group,
Tenovus Research Laboratory, Southampton University Hospitals Trust,
Tremona Rd, Southampton SO16 6YD, UK; e-mail: dz1{at}soton.ac.uk.
| |
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