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Blood, Vol. 94 No. 1 (July 1), 1999:
pp. 244-250
EBNA-1 Gene Sequences in Brazilian and American Patients With
Hodgkin's Disease
By
Karen L. Chang,
Yuan-Yuan Chen,
Wen-Gang Chen,
Kazuhiko Hayashi,
Carlos Bacchi,
Maura Bacchi, and
Lawrence M. Weiss
From Division of Pathology, City of Hope National Medical Center,
Duarte, CA; Department of Pathology, Okayama University Medical School,
Okayama, Japan; and Department of Pathology, State University of Sao
Paulo (UNESP), Botucatu, Brazil.
 |
ABSTRACT |
We examined the types of Epstein-Barr virus-associated nuclear
antigen-1 (EBNA-1) gene carboxy (C)-terminal mutations
occurring in Hodgkin's disease (HD) and reactive tissues from two
different geographic regions. Previously reported EBNA-1 C-terminal
region amino acid sequence variants, based on the amino acid at codon 487, include Prototype (P)-ala, which is found in the B95.8-derived prototype virus, P-thr, Variant (V)-leu, V-val, and V-pro. Using polymerase chain reaction (PCR) to amplify portions of the
EBNA-1 gene, followed by DNA sequencing, we found a single EBNA-1 gene sequence variant in each tissue, whether reactive or neoplastic and
whether from Brazil or the United States. Variant EBNA-1 gene sequences
were more common in both neoplastic and non-neoplastic tissues from
different geographic areas than the so-called prototype sequence. In
the 17 Brazilian HD cases, 4 cases had P-thr variants and 13 had V-leu
variants. In the six reactive tissues from Brazil, one had a P-ala
variant, two had P-thr variants, and three had V-leu variants. In the
12 American HD cases, 2 had P-ala variants, 6 had P-thr variants, and 4 had V-leu variants. The 11 American reactive tissues included 2 P-ala
variants, 5 P-thr variants, and 4 V-leu variants. In both countries,
there were similar variant EBNA-1 sequences present in normal tissues
and HD cases. Compared with the P-ala and P-thr cases, the V-leu cases
were more likely to have the 30-bp latent membrane protein 1 (LMP1) gene deletion (P = 0.0075). In
addition, cases of HD with the V-leu were statistically associated with
a substitution of asparagine for glutamine at codon 322 of the
C-terminal portion of the LMP1 gene. Our results suggest that any
variation in EBNA-1 gene sequence is caused by a polymorphism present
in pre-existing viral strains in the underlying population, and not a
mutation occurring during oncogenesis.
© 1999 by The American Society of Hematology.
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INTRODUCTION |
THE EPSTEIN-BARR VIRUS (EBV) is
associated with a number of malignancies, including Hodgkin's disease
(HD), non-Hodgkin's lymphomas, and nasopharyngeal
carcinoma.1-4 An association between EBV and HD had long
been suspected from early epidemiological and serological
studies.5-8 Demonstration of EBV genomic DNA in HD was
first reported in 1987.9 Subsequent in situ hybridization studies localized the virus to the Reed-Sternberg cells and variants, which are the presumed neoplastic component of HD.1,10-12
Approximately 40% to 50% of cases of classical HD occurring in
immunocompetent individuals are EBV-associated. In EBV-positive HD
cases, the EBV is found in nearly all of the Reed-Sternberg cells,
regardless of methodology.
In an effort to elucidate the pathogenesis of these EBV-related HD
cases, investigators have examined EBV genes with oncogenic potential:
latent membrane protein (LMP), EBV-associated nuclear antigen-1
(EBNA-1), and EBNA-2. A deleted LMP1 gene variant, initially thought to
be important to the pathogenesis of HD, has been reported in equal
frequency in cases of EBV-associated HD and normal tissues in different
ethnic populations.13-18 This observation suggests that
this deletion may not be relevant in the pathogenesis of EBV-associated
HD, at least in immunocompetent patients.
Immunohistochemical studies have detected EBNA-1 protein in cases of
EBV-associated HD.19 Initial molecular studies of EBNA-1 reported the prototype EBNA-1 gene to be extremely rare in malignant tissues.20 In contrast, unique variant EBNA-1 gene
sequences have been found in different malignancies, suggesting that
some EBNA-1 subtypes may play a role in tumorigenesis.21
Furthermore, investigators have also reported the presence of both
prototype and variant EBNA-1 gene sequences in oral secretions and
peripheral blood cells from normal patients, with an EBNA-1 subtype
pattern and frequency different than those reported in various
malignancies.20 However, in a previous study of EBNA-1 gene
sequences in gastric carcinoma, we found the prevalence of variant
sequences in the tumor tissues to be similar to that of reactive
tissues, and also, that each tissue, whether benign or malignant,
harbored a single EBNA-1 subtype.22
Because there are no reported data on EBNA-1 gene deletions in HD, we
examined the different types of EBNA-1 gene carboxy (C)-terminal
mutations occurring in HD and non-HD reactive tissues from patients
living in two different geographic regions. Our results show that (1)
variant EBNA-1 gene sequences are more prevalent in non-neoplastic
tissues than the so-called prototype sequence; (2) similar variant
EBNA-1 sequences are present in normal tissues and HD cases from
Brazil, suggesting that any variation is a result of a polymorphism and
not a mutation; (3) the neoplastic tissues from the United States also
have similar EBNA-1 gene sequences as their reactive counterparts, and
furthermore, are similar to those of the Brazilian tissues, showing
that the different ethnic groups may have similar types of
polymorphisms; (4) only one EBNA-1 subtype is present in each tissue
type, regardless of geographic origin; and (5) the prevalence of the
EBNA-1 gene subtypes is statistically significantly different,
depending on the presence or absence of the LMP1 gene deletion variant
and the presence or absence of a polymorphism at codon 322 of the
C-terminal protion of the LMP1 gene.
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MATERIALS AND METHODS |
Cases.
We studied 29 cases of EBV-associated HD, including 17 cases from
Brazil and 12 cases from the United States. We also studied 17 reactive
lymphoid tissues, including 6 Brazilian cases of either normal
tonsil or nonspecific tonsillitis, 3 American tonsillar cases of reactive hyperplasia, and 8 American HD cases in which the
Reed-Sternberg cells were negative for EBV Epstein-Barr virus-encoded RNA (EBER), but rare small lymphocytes were EBER-positive. The clinical
aspects, histological features, EBV EBER data, the results of LMP1
immunohistochemistry and gene deletion studies, and the EBV type (Type
A or B) have been previously reported.13 The EBNA-1 gene
sequences of the American reactive lymphoid tissues have been
previously reported.22 EBV serological data were not available for any of the patients.
Polymerase chain reaction studies for the C-terminal of the EBNA-1
gene.
The EBNA-1 genotype was analyzed by polymerase chain reaction (PCR)
amplification and subsequent sequence analysis of the C-terminal region
of EBNA-1, which has been previously shown to contain most of the
substitutions seen in the reported variant subtypes.20,21,23 For each case, genomic DNA was extracted from 5-µm sections cut from formalin-fixed, paraffin-embedded tissue
blocks, using 0.2 mg/mL proteinase K digestion buffer overnight, followed by denaturation by boiling. PCR studies were performed with 2 µL of extracted DNA in a 30-µL mixture containing 50 mmol/L KCl, 10 mmol/L Tris buffer (pH 8.3), 50 µmol/L of each deoxynucleotide triphosphate, 2.5 mmol/L MgCl2, 1 U of Taq polymerase
(Perkin Elmer, Foster City, CA), and 20 pmol of each primer. Two
24-base oligonucleotide primers were used: C1,
5'-GAAATTTGAGAACATTGCAGAAGG-3' and C2, 5'-GGGTCCAGGGGCCATTCCAAA-3'.
After an initial denaturation for 3 minutes at 95°C, 45 amplification
cycles were performed as follows: denaturing at 94°C for 30 seconds,
annealing at 58°C for 30 seconds, and extension at 72°C for 40 seconds. A final extension at 72°C for 3 minutes completed the PCR
amplification. The PCR setup and the post-PCR work were performed in
separated laboratories to minimize the possibility of contamination.
PCR studies for the LMP1 gene deletion region.
Using genomic DNA as extracted above, the C-terminal region of the LMP1
gene deletion region was sequenced as above, using two 20-base
oligonucleotide primers: 5'-GGAAATGATGGAGGCCCTCC-3' and
5'-GTAGCTTAGCTGAACTGGGC-3'. For a small subset of samples in which the
initial PCR step yielded no visible gel products, nested PCR
amplification was performed using the following two sets of 20-base
oligonucleotide primers: 5'-CGGAAGAGGTGGAAAACAAA-3' and
5'-GTGGGGGTCGTCATCATCTC-3'. The PCR conditions and amplification strategies were identical to those listed above.
DNA sequencing.
Thirty microliters of the PCR products were run on a 2% agarose gel,
and the product bands were cut out, purified using a Qiaex gel
extraction kit (Qiagen, Hilden, Germany), and resuspended in 30 µL of
water. The products were sequenced with an AmpliCycle sequencing kit
(Perkin Elmer), using the manufacturer's recommended conditions. The
products of the sequencing reaction were then separated by gel
electrophoresis, dried, and exposed to film. The gel consisted of 7 mol/L urea and 8% polyacrylamide.
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RESULTS |
In this report, we use terminology introduced by Gutierrez et al, who
classified EBV into five subtypes, based on the EBNA-1 amino acid
sequence in the C-terminal region.20 They named the EBNA-1
subtypes according to the amino acid at codon 487 (Fig 1). Two closely related prototype strains
were identified, named by their difference in the amino acid at codon
487 (Prototype [P]-ala, with alanine at codon 487, is found in the
B95.8-derived virus; P-thr differs by the presence of threonine at
codon 487). They identified three additional EBNA-1 variants (V),
termed V-pro, V-leu, and V-val, because of proline, leucine, or valine,
respectively, at codon 487 instead of alanine. In addition, we continue
terminology used in our previous report of EBNA-1 gene sequences in
gastric carcinoma.22
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| Fig 1.
Detailed sequence data of the carboxy fragment of EBNA-1
amplified from Brazilian and American EBV-associated Hodgkin's disease
and non-EBV-associated Hodgkin's disease and reactive tissues.
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Using PCR to amplify fragments of the EBNA-1 gene, followed by gene
sequencing, we identified EBNA-1 gene sequence variants in all 17 cases
of known EBV-positive HD from Brazil (Table
1). Each case contained only a single
EBNA-1 gene sequence. None of the Brazilian cases had the prototype
P-ala sequence. Three of the HD cases had a gene sequence that resulted
in the same amino acid sequence published by Gutierrez as
P-thr.20 The gene sequence was identical to the P-thr
sequence detected in clones of a single nasal lymphoma in another
report from the same group.24 Compared with the prototype
P-ala EBNA-1 gene, the P-thr sequence differed by three amino acid
substitutions, at codons 487, 492, and 524, and two silent base changes
at codons 499 and 520. Another case had the same changes as P-thr, with
an additional point mutation at codon 525; we named this P-thr". This
variant sequence was also identified in a previous study of nasal
lymphomas.24 Twelve of the Hodgkin's cases from Brazil had
an EBNA-1 gene sequence that differed from the prototype P-ala by eight
codon changes, including seven amino acid substitutions at codons 487, 492, 499, 500, 502, 524, and 525, and a silent mutation at codon 520. These 12 nonprototype cases had the same amino acid sequence as the V-leu variant previously described by Gutierrez et al,20
and furthermore, they had the same gene sequence identified as V-leu in
the nasal lymphoma study of Gutierrez.24 The final
Brazilian HD case had an EBNA-1 gene sequence that was similar to
V-leu, with an additional point mutation at codon 511. We named this variant as V-leu". This variant has not been previously described.
The six reactive tissues from Brazil also each had a single EBNA-1 gene
sequence that differed from the P-ala prototype gene sequence. One
reactive tissue differed from the P-ala prototype by two amino acid
substitutions at codons 499 and 524, and we named this as
P-alaIV. This variant has also not been previously
described. Two reactive Brazilian tissues had the P-thr EBNA-1 gene
sequence. The V-leu EBNA-1 gene sequence was identified in the
remaining three reactive Brazilian tissues.
Of the 12 cases of North American HD, only one case had the prototype
P-ala gene sequence. Another case had an EBNA-1 gene sequence with two
amino acid substitutions at codons 499 and 524, which was named P-ala".
This sequence was previously observed in our study of EBNA-1 gene
sequences in gastric carcinomas.22 Six American HD cases
had the P-thr amino acid sequence, and four others had the V-leu amino
acid sequence (Fig 2).
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| Fig 2.
This is a sequence gel of one of the cases of North
American Hodgkin's disease; this is the minus strand of the V-leu
variant. This shows a change from thymine to guanine at codon 520, from
guanine to alanine at codon 524, and from guanine to cytosine at codon
525.
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None of the 11 reactive American tissues contained the prototype P-ala
gene sequence. Two of the reactive tissues each had a different P-ala
variant of the prototype sequence, including P-ala" and P-ala , both
of which were observed in our previous study of EBNA-1 gene sequences
in gastric carcinomas.22 Four other reactive American
tissues had the same P-thr gene sequence that was identified in three
cases of Brazilian HD, and another patient had a different variant of
P-thr, with four amino acid substitutions at codons 487, 492, 499, and
524, and a silent base change at codon 520, which we named as P-thr'.
This P-thr' sequence was previously reported in a study of nasal
lymphomas.24 Another four patients had the V-leu sequence.
For all of these tissues, the most frequent substitutions were
identified at codons 499 and 524. Identical substitutions were found at
both of these codons in all of the Brazilian and American tissues,
whether reactive or malignant. Other frequently substituted sites were
codons 492 and 520. Both were affected with identical substitutions in
the Brazilian and American tissues in equally high frequency. Codons
500, 502, and 525 were less frequent sites of mutation; these were seen
in much higher frequency in the Brazilian tissues when compared with
the American tissues. Again, all of the substitutions were identical.
Codon 511 was the site of mutation in a single Brazilian HD case.
Table 2 shows the frequency of the LMP1
gene deletion with the different EBNA-1 gene sequence variants.
Seventy-three percent of the cases previously shown to have the LMP1
gene deletion variant13 had the V-leu EBNA-1 subtype (16 of
22), whereas 67% of cases previously shown to have the nonmutated LMP1
gene had one of the prototype EBNA-1 gene sequence variants. This
difference was statistically significant (P = .0075), even
when comparing the V-leu cases with P-ala and P-thr cases separately
(P < .03).
Table 3 shows the EBV LMP1
deletion region polymorphisms for the 46 cases. The 2-bp
change resulting in substitution of asparagine (Asn) for glutamine at
codon 322 of the C-terminal portion of the LMP1 gene was found to be
statistically significant more frequently in tissues that had the V-leu
EBNA-1 subtype (14 of 21, 67%). Wildtype LMP1 was more frequently
identified in tissues with the P-thr EBNA-1 subtype; this was
statistically significant (10 of 13, 77%). Seven of 10 (70%)
Brazilian HD cases previously shown to have the V-leu EBNA-1 subtype
had the Asn amino acid substitution for glutamine. In contrast, none of
the four Brazilian HD cases previously shown to have the P-thr EBNA-1
subtype had any LMP deletion region polymorphisms. This difference was
statistically significant (P < 0.02). Furthermore, three of
four (75%) American HD cases that were previously shown to have the
V-leu EBNA-1 subtype also had the Asn amino acid substitution at codon
322 of the C-terminal portion of the LMP1 gene. In contrast, only one
of six P-thr American HD cases (17%) had the Asn amino acid
substitution, with the other five P-thr cases consisting of three
wildtype LMP1 cases and two cases with a single base pair substitution.
Four of the seven (57%) reactive cases (both countries) previously
identified as V-leu also had the Asn amino acid substitution, in
contrast to three of five (60%) reactive P-thr cases having the
wildtype LMP1 gene. In these reactive cases, the tendency for a
particular EBNA-1 subtype to have a specific LMP1 deletion region
polymorphism was not statistically significant, perhaps because of the
low numbers of cases.
As previously published, only four of the tissues had EBV Type B; the
rest were Type A.13 Three of the four Type B tissues had
the V-leu EBNA-1 gene sequence; the other had the P-ala" gene sequence.
There was no statistically significant difference in EBV Type A or Type
B, when compared with the different EBNA-1 gene sequence variants.
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DISCUSSION |
EBNA-1 is a nuclear antigen that is essential for the maintenance of
the Epstein-Barr viral episome. It is also the only viral protein
required for replication of the latent form of EBV.25,26 Relative to the C-terminal region of the Epstein-Barr prototype virus
B95.8, several variants of the EBNA-1 gene sequence have been
identified.20-22,27,28 These variants have been reported in
non-Hodgkin's lymphomas, nasopharyngeal carcinomas, gastric carcinomas, and/or cell lines known to carry monoclonal EBV, in equal
frequency in Type I and Type II EBV strains.
Our data on EBNA-1 gene sequences in HD and reactive tissues from
Brazilian and American patients differ from previously published EBNA-1
gene sequence data in non-Hodgkin's lymphomas and other malignancies
in several ways. First, we found a single variant EBNA-1 sequence in
each of the reactive tissues, in contrast to the finding of multiple
EBNA-1 sequences in oral secretions and peripheral blood samples of
normal patients by Gutierrez et al,20 and also in contrast
to the finding of two clones of spontaneously derived EBV-containing
B-cell lines, each with a different subtype, obtained from a single
healthy individual by Wrightham et al.28 We hypothesize
that this difference may be because of site-specific EBV reservoirs,
with analysis of amplified DNA from oral secretions and peripheral
blood lymphocytes allowing for sampling of viral reservoirs containing
both free and cell-associated virus, whereas amplified DNA from tissue
samples contains only cell-associated EBV.
Second, we found EBNA-1 gene sequences in reactive tissues that are
similar to those in malignant tissues from the same ethnic population.
This finding suggests that observed variations in EBNA-1 gene sequences
are a result of polymorphisms present in the resident EBV strain(s) in
a population and not caused by mutations occurring during pathogenesis.
These results differ from those of Bhatia et al, for whom one variant
subtype was seen only in Burkitt lymphoma cases and not in any samples
of normal peripheral blood lymphocytes in two different ethnic
groups.21 These results also differ from Gutierrez et al,
who found different EBNA-1 sequence alterations in Hong Kong
nasopharyngeal carcinomas than those detected in normal Hong Kong
peripheral blood lymphocytes.20 However, these results are
similar to our previous study of gastric carcinoma, in which the gene
sequences in reactive and malignant tissues were identical or similar
in the same ethnic population.22 In addition, in the study
of Gutierrez et al, selected normal oral secretions from Hong Kong
patients contained similar EBNA-1 amino acid sequences as the
nasopharyngeal carcinoma tissues.20
Third, the EBNA-1 gene sequences found in Brazilian patients were
similar to those found in American cases, showing that EBNA-1 gene
sequences can be preserved in ethnically diverse but geographically separated populations. Previous studies also found similarities in
prevalence and type of LMP gene deletions between these two geographically distinct populations.13
Interestingly, the EBNA-1 gene subtype was shown to be statistically
significantly different, depending on whether the tissue had the LMP1
gene deletion or not. In addition, the presence of a specific LMP1
deletion region polymorphism was shown to be different depending on
which EBNA-1 gene subtype the patient harbored. This was shown to be
statistically significantly different for the cases of Brazilian and
American HD, and the trend was also observed in cases of reactive
tissues, whose numbers are too small to approach statistical
significance. Although the mere presence of the LMP gene deletion is
not indicative of a specific EBV strain, the sequence polymorphisms in
the C-terminus of the LMP1 gene, an area that incorporates the deletion
region, have been previously shown to be a reliable sequence for strain
identification.29
Similar to other tissue studies, we identified only a single EBNA
subtype in each tumor, regardless of ethnic origin. This is similar to
previous studies of EBV-associated Burkitt lymphoma and nasopharyngeal
carcinoma, in which the malignant tissues always contained a single
EBNA-1 variant.20,21 However, our observation is in marked
contrast to a recent report that documented multiple EBNA-1 subtypes in
33 of 39 nasal lymphomas.24 In that study, the presence of
prototype EBNA-1 in conjunction with one to two variant EBNA-1 gene
sequences was reported in all 33 nasal lymphomas. One could postulate
that this difference in the observed number of EBNA-1 subtypes in
tissue may also be site specific. One can easily imagine non-neoplastic
EBV-infected oropharyngeal secretions "contaminating"
nasopharyngeal biopsy samples, which must pass through the oropharynx
or nasopharynx during the surgery; this would result in the
amplification of multiple EBNA-1 variants. In contrast, tissues
surgically removed from other anatomic sites not "passing
through" the oropharynx or nasopharynx may result in amplification
of only one cell-associated EBV subtype. However, our study also
included some tissues from the nasopharynx, and thus, site-specific
differences cannot fully explain the observed difference in number of
EBNA-1 subtypes in tissue. We believe that the single variant strain in
our cases reflects a "tissue-invasive" form of EBNA-1, and thus,
it may be the strain most relevant to tumorigenesis.
We also found that variant EBNA-1 sequences are far more common in
non-neoplastic tissues from different ethnic populations than the
so-called prototype sequence. All of the reactive tissues had EBNA-1
C-terminal gene sequences that differed from the published B95.8 EBNA-1
gene sequence. Previous studies of healthy patients document
predominance of the prototype EBNA-1 sequence, frequently in
association with a variant EBNA-1 sequence; these studies were performed in body fluids and did not include non-neoplastic tissues. One group reported EBNA-1 antigen variants in 50% of lymphoblastoid cell lines established from normal EBV-seropositive volunteers from the
United States and the United Kingdom.28 In contrast, another group reported the prototype P-ala amino acid sequence to be
the most frequent EBNA-1 subtype in peripheral blood lymphocytes of
healthy people, but the P-ala was usually present in conjunction with
variant virus sequences.21 Based on our findings, we
conclude that the incidence of the prototype sequence is not high in
non-neoplastic solid tissues.
The reactive tissues from Brazil and the United States showed either a
P-ala variant, P-thr or a P-thr variant, or V-leu or a V-leu variant.
Previously identified EBNA-1 variants, V-val and V-pro, were not
identified in any of the reactive cases.21 We propose that
the lack of detectable V-pro and V-val subtypes indicates that these
subtypes are not common in the resident population of these geographic areas.
In this study, all of the Brazilian and American HD cases had variant
EBNA-1 gene sequences (P-ala variants, P-thr and variants, and V-leu
and variants), regardless of whether they were from North or South
America. This is similar to previous studies of cases of American and
African Burkitt lymphomas, in which the P-ala sequence was found in a
small minority of cases.21 This is also similar to the
study of nasal lymphomas, in which all 39 tumors had at least one
variant EBNA-1 gene sequence.24 In addition, one study
reported nonprototypic EBNA-1 gene sequences in all seven Hong Kong
nasopharyngeal carcinoma tissues, as well as in a nasopharyngeal
carcinoma cell line and a B-lymphoblastoid cell line.27
Furthermore, these results are similar to our previous study of EBNA-1
gene sequences in gastric carcinomas, in which variant EBNA-1 sequences
were exclusively found in Japanese tumors and in 88% of American
carcinomas.22 In the current study, we found only two
EBNA-1 variants (P-thr" and V-leu") exclusively in malignant tissues.
However, our numbers are too low (each in a different case of Brazilian
HD) to draw any significant conclusions regarding these two EBNA-1 variants.
| |
FOOTNOTES |
Submitted September 16, 1998; accepted February 23, 1999.
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 Karen L. Chang, MD, Division of Pathology,
City of Hope National Medical Center, 1500 E Duarte Rd, Duarte, CA
91010-0269.
| |
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