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A micro-array analysis using biopsies from patients with EBV-positive undifferentiated nasopharyngeal carcinoma (NPC) and from cancer-free controls revealed down-regulation of tumour suppressor genes (TSG) not previously associated with this disease; one such gene was the ataxia telangiectasia mutated (ATM) gene. Q-PCR confirmed down-regulation ofATMmRNA and ATM protein expression in tumour cells was weak or absent in almost all cases. In NPC cell lines, however,ATMwas down-regulated only in the EBV-positive line, C666.1, and in none of five EBV-negative lines.In vitroinfection of EBV-negative NPC cell lines with a recombinant EBV was followed by the down-regulation ofATMmRNA and protein, and only EBV-positive cells showed a defective DNA damage response following γ-irradiation. Our data suggest that loss ofATMfunction could be an important step in the pathogenesis of NPC, and may have implications for the treatment of this disease. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.