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Znt. J. Cancer: 66,711-712 (1996)
0 1996 Wiley-Liss, Inc.
Publication of the International Union Against Cancer
Publicationde I’Union Internationale Contre le Cancel
LETTER TO THE EDITOR
Dear Sir,
Prevalence of LMPl deletion variant of Epstein-Barr virus in nasopharyngeal carcinoma and gastric tumors in Hong
Kong
Chang et al. (1995) have described a prevalent strain of
Epstein-Burr virus (EBV) associated with T-cell lymphoma
and nasophayngeal carcinoma (NPC) in the Taiwanesepopulation. The strain was identical to a previously reported NPCEBV strain from a cell line -1510 originatingfrom Taiwan,
which showed Xho I restriction enzyme polymorphism in exon
1 and a 30-bp deletion in exon 3 of the latent membrane
protein 1 (LMP1) gene (Chang et al., 1995 Chen et al., 1992).
We have also identified a prevalent EBV strain (HKNPCEBV) in nasopharyngeal carcinoma in Hong Kong, where the
incidence of this cancer is high. The sequence of the LMPl
gene of this prevalent strain is basically similar to that reported
by Chang et al. (1995)but with some specijic differences.
We examined 74 NPC primary biopsies from Southern
Chinese patients in Hong Kong and 3 NPC xenograjis (HK2117 HK-666 and HK-1915) by PCR-RFLP analysis, and
observed loss of the Xho I site in exon I of the LMPl gene in all
NPC biopsies and xenograjis. A 30-bp deletion at the C-termind region was also identified in 69/ 74 (93%) biopsies and
313 (100%)xenografts. Upon SSCP and direct DNA sequencing analysis, a prevalent strain with a specific sequence of the
LMPl gene was observed in 64174 (86%) biopsies and 213
xenograjis (HK-2117and HK-666). This sequence was characterized by a 30-bp deletion at codons 346 to 355 (nt 168285 to
168256), and a unique G to A mutation at codon 335 (nt
168317, GGC to GAC), resulting in a change of amino acid
from glycine to aspartic acid. The 30-bp deletion site was
similar to that reported for the NPC-CAO strain which had a
Northern Chinese origin (Hu et al., 1991), but differsfrom that
of the Taiwanese strain with deletion site at nt 168282 to
168253 reported by Chang et al. (1995). Otherwise, mutations
at codon 322 (CAA t o w ) , 334 (CAG to CGG), 338 (TTG
to TCG) and 342 (GGA to GGT) were identical to those seen
in the Taiwanese strain. The mutational change at codon 335,
however, has not been reported previously in either the NPCCAO strain from Northern China or NPC-1510 strain from
Taiwan.
Furthermore, 2 other minor EBVstrains (I and II) were also
identijied in our NPC biopsies. The first of these minor strains
(I), found in 5174 (7%) biopsies and one xenograft (HK1915), did not have the afore-mentioned base substitution at
codon 335, although the 30-bp deletion and codon changes in
the C-terminus of the LMPl gene were otherwise the same as
in the prevalent gpe. The second minor strain (II), found in
5/74 (7%) NPC biopsies, did not have the 30-bp deletion at
the C-terminus, although loss of the Xho I site at the N-ter-
minus was found in all these cases. This minor strain II also
consistently exhibited base substitutions at codon 331, 338,
342,344 and 355.
To determine whether the prevalent EBV strain in our NPC
biopsies could be found in other EBV-related tumors in Hong
Kong, we also investigated tumor tissues of 6 gastric carcinomas and 5 gastric lymphomas which showed positivity on
EBERl. Loss of the Xho I site at the N-terminus was found in
all cases, and 10111 cases had a 30-bp deletion. Among these
10 cases, 2 carcinomas and 2 lymphomas contained the
prevalent HKNPC-EBV strain. One other carcinoma and 2
lymphomas contained the minor strain I with absence of base
substitution at codon 335. Three other cases had novel mutational changes at codons 333, 336 and 343 respectively, in
addition to changes at codons 334, 338 and 342 as in the
minor strain I. Although the sequence changes in the LMPl
gene in the EBV-associated gastric carcinomas and lymphomas were basically similar to those associated with NPC, more
sequence variations were found in the strains associated with
gastric tumors.
Thefrequency of the HKNPC-EBVprevalent strain was also
investigated in the throat washings of 13 “healthy”individuals
in Hong Kong. These “healthy’’ individuals were disease-free
close relatives of existing NPC patients. Loss of Xho I at the
N-terminus was found in all cases. Eleven cases had the 30
bp-deletion at the C-terminus codons 346 to 355, with 8 cases
having changes at codons 334, 335, 338 and 342 as in the
prevalent HKNPC-EBVstrain. The LMPl gene sequence in 3
cases corresponded to that of minor strain I without the base
substitution at codon 335. There were 2 cases of throat washings from these healthy individuals having 2 types of LMPl
sequence, with one case having the minor strains I and II, and
the other case the prevalent strain and minor strain II. Vasef et
al. (1995) have reported 2 cases of EBV-positive HodgkinS
disease showing 2 LMPl variants in different sites of the
disease. The authors suggested that the discordance between
anatomic sites might occur as a late mutational event, after
disease dissemination. Since we were examining the throat
washings of healthy individuals, double infection may be the
explanationfor the detection of the 2 LMPl strains in the same
site. Thus, both the prevalent and minor strains of the EBVLMPl gene found in NPC in Hong Kong could also be found
in the throat washings of healthy individuals in Hong Kong.
Table I summarize these data.
Upon comparing our data with those of Chang et al. (1995),
we conclude that similar prevalent LMPl variants are present
712
CHEUNG ETAL.
TABLE I -COMPARISON OF THE EBV-LMP1 GENE C-TERMINUS AT SPECIFIC REGION AMONG NPC FROM DIFFERENT SOURCES. THE SEQUENCE OF
THAT OF B95.8 CELL LINE IS INCLUDED AS REFERENCE
Amino acid (nucleotide)
Source of tissueicell line
B95.8
NPC (Northern China)
NPC 'Taiwan)
NPC {Hong Kong)
CAO
1510
Prevalent
Minor I
Minor I1
CAA
AAT
AAA
AAA
AAA
CAA
CAG
CGG
CGG
CGG
CGG
CAG
335 (168317)
GGC
GGC
GGC
GAC
GGC
GGC
338 (168308)
342 (168295)
TTG
GGA
GGT
GGT
GGT
GGT
GGT
TCG
TCG
TCG
TCG
CCG
Amino acid (nucleotide)
Source of tissuelcell line
B95.8
NPC Northern China)
NPC {Taiwan)
NPC (Hong Kong)
334 ~168320)
322 (168357)
CAO
1510
prevalent
minor I
minor I1
344 11682901
146 (1682851
347 (168282)
355 11682561
356 (168253)
357 (1682501
GGT
GGT
GGT
GGT
GGT
GAC
CAT
AGT
GGT
GAT
GAT
CCA
CCA
CCA
CCA
CCA
CCA
< .........................................................
>
< ...........................................................
CAT
< ...........................................................
>
< ..........................................................
CAT
ACT
>
GCT
>
GAT
GAT
GAT
The EBV-LMPl prevalent strain found in Hong Kong NPC accounted for 86% of all cases with a 30-bp deletion at codon 346-355 and
codon changes at 322,334,335,338 and 342. The change a t codon 335 has not been reported for the NPC-CAO strain from Northern
China or the 1510 strain from Taiwan. The minor strain I had a sequence similar to that of the prevalent type but without the change at
codon 335. The minor strain I1 did not have the 30-bp deletion and had base changes at other codons. (<. ....>) denotes the 30-bp
deletion region.
in Taiwan and in Hong Kong. Moreover, they are also in line
with those reported by Knecht et al. (1995) which showed
nearly identical mutational hot-spots in the particular LMPl
region in lymphomasfrom a Europeanpopulation. The similar
base substitutions and the 30-bp deletion in the C-terminus of
the LMPl gene of these strains may correlate with specific
major histocompatibility complex haplotypes of the Chinese
population in the 2 geographical areas. It has been postulated
that the prevalent type of LMPl gene allows the virus to escape
immunosuweillence, contributing to the high incidence of
some EBV-associated tumors in this part of the world. The
signiJcance of the base substitution at codon 335 of the LMPl
gene found in the prevalent strain of EBV in Hong Kong is still
not clear, and calls for further comparative studies of the
different LMPl strains of EBV in our population, in terms of
theirpathogenic potential and prognostic impact on the tumors
associated with them.
Yours sincerely,
Siu-Tim CHEUNG!Kwok-Wai Lo1, S.F. LEUNG~,
Wing-Yee
CHAN~,
Peter H.K. CHOI~,
P.J. JOHN SON^, Joseph C.K. LEE^
and Dolly P. H U A N ~ ~
Departments of 'Anatomical and Cellular Pathology and
2ClinicalOncology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of WalesHospital, Hong Kong.
February 12,1996.
3To whom correspondence and reprint requests should be addressed. Fax: (852) 26376274.
REFERENCES
CHANG,
Y.-S., Su, I.-J., CHUNG,
P.-J., SHU,C.-H., NG, C.-K., Wu, S.-J.
and LUI. S.-T.. Detection of an Eustein-Barr virus variant in T-cell
lymphoma tissues identical to the d'istinct strain observed in nasopharyngeal carcinoma in the Taiwanese population. Int. J. Cancer, 62,
613-617 (1995).
CHEN,M.-L., TSAI,C.-N., LIANG,C.-L., SHU,C.-H., HUANG,C.-R.,
SULITZEANU,
D., LIU,S.-T. and CHANG,
Y.-S., Cloning and characterization of the latent membrane protein (LMP) of a specific EpsteinBarr virus variant derived from the nasopharyngeal carcinoma in the
Taiwanese population. Oncogene, 7,2131-2140 (1992).
E.R., C H ~ NF.,
, CAO, S.-L., ERNBERG, I.,
HU, L.-F., ZABAROVSKY,
KLEIN,G. and WINBERG,
G., Isolation and sequencing of the EpsteinBarr virus BNLF-1 (LMP1) from a Chinese nasopharyngeal carcinoma. J. gen. ViroL, 72,2399-2409 (1991).
m E C H T , H., BACHMANN,
E., BROUSSET,P., ROTHENBERGER, s.,
EINSELE,H., LESTOU,V.S., DELSOL,G., BACHMANN,
F., AMBROS, P.F.
and ODERMATT,
B.F., Mutational hot-spots within the carboy terminal region of the LMPl oncogene of Epstein-Barr virus are frequent in
lymphoproliferative disorders. Oncogene, 10,523-528 (1995).
L.J. and WEISS,
VASEF,M.A., KAMEL,O.W., CHEN,Y.-Y., MEDEIROS,
L.M., Detection of Epstein-Barr virus in multiple sites involved by
Hodgkin's disease. Amer. J. Pathol., 147,1408-1415 (1995).
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