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Genes Involved in DNA Repair and Nitrosamine Metabolism and Those Located on Chromosome 14q32 Are Dysregulated in Nasopharyngeal Carcinoma

¹ Biometric Research Branch, Division of Cancer Treatment and Diagnosis and ² Hormonal and Reproductive Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute; ³ Westat, Inc., Rockville, Maryland; ⁴ Institute for Molecular Virology, ⁵ Department of Statistics and of Biostatistics and Medical Informatics, and ⁶ McArdle Laboratory for Cancer Research and Howard Hughes Medical Institute, University of Wisconsin, Madison, Wisconsin; ⁷ Department of Otolaryngology, McKay Memorial Hospital; ⁸ Graduate Institute of Epidemiology, College of Public Health, National Taiwan University, Taipei, Taiwan; and ⁹ Department of Pathology, Johns Hopkins University, School of Medicine, Baltimore, Maryland

Requests for reprints: Allan Hildesheim, National Cancer Institute, 6120 Executive Boulevard, Room 7062, Rockville, MD 20852. Phone: 301-435-3984. E-mail: hildesha{at}exchange.nih.gov

Polymorphisms in nitrosamine metabolism, DNA repair, and immune response genes have been associated with nasopharyngeal carcinoma (NPC). Studies have suggested chromosomal regions involved in NPC. To shed light on NPC etiology, we evaluated host gene expression patterns in 31 NPC and 10 normal nasopharyngeal tissue specimens using the Affymetrix Human Genome U133 Plus 2.0 Array. We focused on genes in five a priori biological pathways and chromosomal locations. Rates of differential expression within these prespecified lists and overall were tested using a bootstrap method. Differential expression was observed for 7.6% of probe sets overall. Elevations in rate of differential expression were observed within the DNA repair (13.7%; P = 0.01) and nitrosamine metabolism (17.5%; P = 0.04) pathways. Differentially expressed probe sets within the DNA repair pathway were consistently overexpressed (93%), with strong effects observed for PRKDC, PCNA, and CHEK1. Differentially expressed probe sets within the nitrosamine metabolism pathway were consistently underexpressed (100%), with strong effects observed for NQ01, CYP2B6, and CYP2E1. No significant evidence of increases in rate of differential expression was seen within the immune/inflammatory pathway. A significant elevation in rate of differential expression was noted for chromosome 4p15.1-4q12 (13.0%; P = 0.04); both overexpression and underexpression were evident (38% and 62%, respectively). An elevation in the rate of differential expression on chromosome 14q32 was observed (11.3%; P = 0.06) with a consistent pattern of gene underexpression (100%; P < 0.0001). These effects were similar when excluding late-stage tumors. Our results suggest that nitrosamine activation and DNA repair are important in NPC. The consistent down-regulation of expression on chromosome 14q32 suggests loss of heterozygosity in this region. (Cancer Epidemiol Biomarkers Prev 2006;15(11):2216–25)

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