Affiliations of authors: M. I. Gutiérrez, M. M. Ibrahim, K. Bhatia, Research Centre, King Fahad National Childrens Cancer Centre and Research, Riyadh, Saudi Arabia; S. E. Straus, J. K. Dale, Laboratory of Clinical Investigation, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
Correspondence to: Kishor Bhatia, Ph.D., King Faisal Specialist Hospital, P.O. Box 3354, MBC 98-16, Riyadh 11211 Saudi Arabia (e-mail: kishor_ bhatia{at}kfshrc.edu.sa).
Tong et al. have extended the study related to BZLF1 polymorphic variants of EpsteinBarr virus (EBV) to samples from Hong Kong and Southern China. This study is of special interest because it incorporates malignant and nonmalignant samples from regions that are endemic for nasopharyngeal carcinoma (NPC). Their observations both confirm and contradict several conclusions from our study (1). First, they provide independent confirmation of the existence of the Zp-P and Zp-V3 variants in another geographic region. Our earlier observations suggested that Zp variants segregated strongly by EBV type, with type B virus exclusively associating with Zp-V3 and type A virus often associating with Zp-P. Exceptions were noted in samples from Far East Asia, which contained type A virus with a Zp-V3 sequence, suggesting that type A Zp-V3 may be prevalent in this geographic region. Tong et al. confirm these findings and validate the existence and the prevalence of the type A Zp-V3 variant in the Southeastern Asian population.
Type B virus is generally considered to be more readily inducible than the type A virus (2). We have speculated that the association of a virus with malignant and nonmalignant lesions is influenced by the lytic potential of the viral types, which in turn may be dictated by the variation in Zp. Tong et al. found a statistically significant association between type A Zp-V3 and NPC. One possible interpretation of these observations would be that a type A Zp-P variant is more responsive to lytic induction than a type A Zp-V3 variant. However, additional regulatory elements beyond Zp also modulate BZLF1, and the possibility that variations in these regions occur between type A Zp-P and type A Zp-V3 needs to be considered.
Several important differences also arise between our observations (1) and those of Tong et al. For example, there is the complete absence of Zp-V4 in their samples. We identified 53 Zp-V4 variants among our nonmalignant samples. It is highly unlikely that these differences are merely technical. An important element in these two studies pertains to the origin of the samples. Our samples from South and North America, Saudi Arabia, and Japanall regions non-endemic for NPC (3)contained EBV with a Zp-V4 variant. If indeed the prevalence of Zp-V4 is geographically restricted, it raises important epidemiologic considerations that may affect the pathogenesis of EBV-associated malignancies. If the absence of Zp-V4 in tumors reflects lower oncogenic potential, the diminished prevalence of this strain in a population endemic for EBV-associated malignancies is of notable interest. Additional studies from other endemic and non-endemic areas are required to establish these associations.
The apparent mutual exclusivity of Zp-V4 and Zp-V3 EBV in non-endemic and endemic populations, respectively, is intriguing. Given the low levels of EBV DNA in nonmalignant samples, the possibility that Zp-V3 and Zp-V4 variants are present at undetectable levels cannot be ruled out. Furthermore, the identification of other variantsalbeit at low frequencyraises the possibility that ongoing mutational events may indeed play a role in the genesis of such variations (4).
REFERENCES
1 Gutiérrez MI, Ibrahim MM, Dale JK, Greiner TC, Straus SE, Bhatia K. Discrete alterations in the BZLF1 promoter in tumor and non-tumor-associated Epstein-Barr virus. J Natl Cancer Inst 2002;94:175763.
2 Buck M, Cross S, Krauer K, Kienzle N, Sculley TB. A-type and B-type Epstein-Barr virus differ in their ability to spontaneously enter the lytic cycle. J Gen Virol 1999;80:4415.[Abstract]
3 Waterhouse JAH, Muri C, Shanmugaratnam K. Cancer incidence in five continents. Vol. V. Lyon (France): International Agency for Research on Cancer (IARC) Sci Publ 1987(88). p. 42.
4 Gutiérrez MI, Spangler G, Kingma D, Raffeld M, Guerrero I, Misad O, et al. EBV in nasal lymphomas contains multiple ongoing mutations in the EBNA-1 gene. Blood 1998;92:6006.
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