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Consistent Sequence Variation of Epstein-Barr Virus Nuclear Antigen 1 in Primary Tumor and Peripheral Blood Cells of Patients with Nasopharyngeal Carcinoma¹

Department of Basic Medicine, Hung Kuang Institute of Technology, Taichung [W-Y. W.]; Department of Biology, National Changhua University of Education, Changhua [Y-C. C., C-M. C.]; Department of Radiation Oncology, Taichung Veterans General Hospital, Taichung [J-C. L., J-S. J.]; Institute of Clinical Medicine, College of Medicine, National Yang-Ming University, Taipei [J-C. L.], Taiwan

Purpose: Nasopharyngeal carcinoma (NPC) has been provenas a cancer associated with Epstein-Barr virus (EBV). This study was performed to examine sequence variations of the EBV nuclear antigen 1 gene (EBNA-1) in primary tumor and peripheral-blood cells of NPC patients from Taiwan.

Experimental Design: DNA extracted from freshly frozen tumor tissues and corresponding peripheral-blood cells of 13 previously untreated NPC patients were subjected to PCR and direct sequencing using EBNA-1-specific primers. We compared the sequence data and analyzed the clinical outcomes.

Results: We obtained a 100% positive-detection rate of EBV DNA in the primary tumors of all patients irrespective of the degree of differentiation. The EBNA-1 gene of all tumor samples was the "V-val" strain, showing the same clustered point mutations. They included 21 nucleotide exchanges, leading to 14 amino-acid mutations and 6 silent exchanges, relative to B95-8 cell line. Two of 13 tumors exhibited an additional point mutation at codon 585. EBV DNA was also detected in peripheral-blood cells of 9 of 13 patients under our experimental conditions. Direct-sequencing data showed match alterations of EBNA-1 gene between the primary tumor and peripheral-blood cells. Tumor relapse was observed in four of nine patients with detectable EBNA-1 DNA in their peripheral-blood cells, whereas none of the four patients without detectable EBNA-1 DNA in their peripheral-blood cells developed tumor relapse.

Conclusions: Results of the current study represents the first demonstration of consistent sequence variation of EBNA-1 in primary tumors and peripheral-blood cells. Clinical observations support that the presence of EBV DNA in the peripheral-blood cells may arise from disseminated cancer cells, resulting in a higher relapse rate and poor prognosis.

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