Background: Head and neck squamous cell carcinoma (HNSCC) is commonly associated with tobacco and alcohol exposures, although dietary factors, particularly folate, and human papillomavirus, are also risk factors. Epigenetic alterations are increasingly implicated in the initiation and progression of cancer. Genome-wide (global) hypomethylation seems to occur in early neoplasia and is a feature of genomic DNA derived from solid tumor tissues, including HNSCC. This study aimed to determine whether global methylation in DNA derived from whole blood, a proxy tissue, is associated with HNSCC and to assess potential modification of this property by environmental or behavioral risk factors. Methods: Global DNA methylation levels were assessed using a modified version of the combined bisulfite
Inactivation of the p16INK4A (CDKN2A) gene in the Rb pathway is among the most common somatic alterations observed in tobaccorelated solid tumors, including head and neck squamous cell carcinoma (HNSCC). In addition, a low folate diet is an important risk factor for HNSCC. Decreased dietary folate in an animal model of hepatocellular carcinoma has been associated with the induction of epigenetic silencing of the p16 INK4A gene. In an ongoing population-based study of HNSCC, we sought to extend this observation to human disease testing the hypothesis that p16INK4A methylation is associated with decreased dietary folate. We also investigated the association of methylation silencing with functional polymorphisms in the folate metabolism enzyme methylene tetrahydrofolate reductase (MTHFR). In 169 HNSCCs, the odds ratio for p16INK4A methylation among those with low dietary folate intake was 2.3 (95% CI 5 1.1-4.8) when compared with those with high folate intake. Furthermore, this increased risk for epigenetic silencing at p16INK4A was modified by the MTHFR alleles previously associated with diminished serum folate levels. Hence, in HNSCC low dietary intake of folate is associated with p16 INK4A methylation, and this relationship is modified by the MTHFR genotype. Our data provides important evidence for a mechanism of action of folate deficiency in cancer. ' 2006 Wiley-Liss, Inc.
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