Bone morphogenetic proteins (BMPs) are an integral component of the TGFb superfamily, responsible for regulation of cell proliferation, differentiation, migration and programmed cell death in a variety of cell types. The BMPs transduce their signals directly through the SMAD family of proteins but they also have been reported to interact with the MAPK and Erk pathways. Inactivation of the BMP pathway genes has been implicated as important in several cancers. Recent work has shown that BMP3b is epigenetically inactivated in cancer and suggests that BMP6 can be epigenetically inactivated. We investigated whether BMP6 is epigenetically inactivated in cell lines and whether BMP3b and BMP6 are epigenetically inactivated in non-small-cell lung cancer (NSCLC). We also studied the relationship between BMP methylation and k-ras mutation. Here, we demonstrate that the BMP3b and BMP6 genes are common targets of epigenetic inactivation in NSCLC, and that they are significantly more likely to be concurrently inactivated (P ¼ 0.009). Furthermore, this coinactivation of BMP3b and BMP6 is significantly associated with mutation of k-ras codon 12 in lung cancer (P ¼ 0.003); those with a k-ras mutation were six times more likely to have concurrent methylation of these BMP loci. Hence, these data suggest that concurrent inactivation of the BMP and activation of the Ras signalling pathways are important in lung carcinogenesis.

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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.

In tobacco-associated solid tumors, evidence suggests that the pattern of carcinogen exposure is related to the nature of somatic gene inactivation within crucial pathways, including the retinoblastoma (Rb) pathway. 1.3 (95% CI, 0.5-3.0) and 1.9 (95% CI, 0.9-4.0) for 29 to 39 years and >39 years of tobacco smoking, respectively, as compared with those that smoked V28 years. As in the case of alcohol use, intensity of tobacco exposure (measured as packs per day) was not associated with gene deletion. Hence, the duration of alcohol use and duration of smoking, but not intensity of either, significantly predicted p16 INK4A homozygous deletion in HNSCC. (Cancer Res 2006; 66(8): 4512-5)