Circulating Concentrations of Vitamin B6 and Kidney Cancer Prognosis: A Prospective Case-Cohort Study

Prospective cohort studies have found that prediagnostic circulating vitamin B6 is inversely associated with both risk of kidney cancer and kidney cancer prognosis. We investigated whether circulating concentrations of vitamin B6 at kidney cancer diagnosis are associated with risk of death using a case-cohort study of 630 renal cell carcinoma (RCC) patients. Blood was collected at the time of diagnosis, and vitamin B6 concentrations were quantified using LC-MS/MS. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated using Cox regression models. After adjusting for stage, age, and sex, the hazard was 3 times lower among those in the highest compared to the lowest fourth of B6 concentration (HR4vs1 0.33, 95% CI [0.18, 0.60]). This inverse association was solely driven by death from RCC (HR4vs1 0.22, 95% CI [0.11, 0.46]), and not death from other causes (HR4vs1 0.89, 95% CI [0.35, 2.28], p-interaction = 0.008). These results suggest that circulating vitamin B6 could provide additional prognostic information for kidney cancer patients beyond that afforded by tumour stage

Aberrant DNA methylation links cancer susceptibility locus 15q25.1 to apoptotic regulation and lung cancer

Nicotinic acetylcholine receptor (nAChR) genes form a highly conserved gene cluster at the lung cancer susceptibility locus 15q25.1. In this study, we show that the CHRNa3 gene encoding the nAChRa3 subunit is a frequent target of aberrant DNA hypermethylation and silencing in lung cancer, whereas the adjacent CHRN f4 and CHRNa5 genes exhibit moderate and no methylation, respectively. Treatment of cancer cells exhibiting CHRNa3 hypermethylation with DNA methylation inhibitors caused demethylation of the CHRNa3 promoter and gene reactivation. Restoring CHRNa3 levels through ectopic expression induced apoptotic cell death. Small hairpin RNA-mediated depletion of nAChRalpha;3 in CHRNalpha;3-expressing lung cancer cells elicited a dramatic Ca2+ influx response in the presence of nicotine, followed by activation of the Akt survival pathway. CHRNalpha;3-depleted cells were resistant to apoptosis-inducing agents, underscoring the importance of epigenetic silencing of the CHRNalpha;3 gene in human cancer. In defining a mechanism of epigenetic control of nAChR expression in nonneuronal tissues, our findings offer a functional link between susceptibility locus 15q25.1 and lung cancer, and suggest nAChRs to be theranostic targets for cancer detection and chemoprevention. \ua92010 American Association for Cancer Research

Quantitative analysis of DNA methylation profiles in lung cancer identifies aberrant DNA methylation of specific genes and its association with gender and cancer risk factors

The global increase in lung cancer burden, together with its poor survival and resistance to classical chemotherapy, underscores the need for identification of critical molecular events involved in lung carcinogenesis. Here, we have applied quantitative profiling of DNA methylation states in a panel of five cancer-associated genes (CDH1, CDKN2A, GSTP1, MTHFR, and RASSF1A)to a large case-control study of lung cancer. Our analyses revealed a high frequency of aberrant hypermethylation of MTHFR, RASSF1A, and CDKN2A in lung tumors as compared with control blood samples, whereas no significant increase in methylation levels of GSTP1 and CDH1 was observed, consistent with the notion that aberrant DNA methylation occurs in a tumor-specific and gene-specific manner. Importantly, we found that tobacco smoking, sex, and alcohol intake had a strong influence on the methylation levels of distinct genes (RASSF1A and MTHFR), whereas folate intake, age, and histologic subtype had no significant influence on methylation states. We observed a strong association between MTHFR hypermethylation in lung cancer and tobacco smoking, whereas methylation levels of CDH1, CDKN2A, GSTP1, and RASSF1A were not associated with smoking, indicating that tobacco smoke targets specific genes for hypermethylation. We also found that methylation levels in RASSF1A, but not the other genes under study, were influenced by sex, with males showing higher levels of methylation. Together, this study identifies aberrant DNA methylation patterns in lung cancer and thus exemplifies the mechanism by which environmental factors may interact with key genes involved in tumor suppression and contribute to lung cancer. ©2009 American Association for Cancer Research

Dietary risk factors for kidney cancer in Eastern and Central Europe

The authors examined the role of diet in the high-risk population of Central Europe among 1,065 incident kidney cancer cases and 1,509 controls in Russia, Romania, Poland, and the Czech Republic. They observed an increased association with kidney cancer for consumption of milk (odds ratio (OR) = 1.46, 95% confidence interval (CI): 1.15, 1.84) and yogurt (OR = 1.34, 95% CI: 1.07, 1.67), as well as all meat (OR = 1.27, 95% CI: 1.06, 1.51 compared with the lowest tertile). High consumption of all vegetables (OR = 0.64, 95% CI: 0.51, 0.80) and cruciferous vegetables (OR = 0.68, 95% CI: 0.55, 0.84) was inversely associated with kidney cancer. In addition, high consumption of preserved vegetables increased the risk of kidney cancer (OR = 1.66, 95% CI: 1.24, 2.21). Alcohol consumption did not appear to be associated with kidney cancer. This 1999-2003 study provides further evidence that diet may play a role in the development of kidney cancer, with a particularly strong protective association for high vegetable intake. The increased risk associated with dairy products, preserved vegetables, and red meat provides clues to the high rates of kidney cancer in this population. Copyright \ua9 2007 by the Johns Hopkins Bloomberg School of Public Health All rights reserved

Vitamin D receptor polymorphisms and renal cancer risk in Central and Eastern Europe

Previous studies investigated the role of vitamin D intake and cancer risk. The kidney is a major organ for vitamin D metabolism, activity, and calcium homeostasis; therefore, it was hypothesized that dietary vitamin D intake and polymorphisms in the vitamin D receptor (VDR) gene may modify renal cell carcinoma (RCC) risk. Three common VDR gene polymorphisms (BsmI, FokI, TaqI) were evaluated among 925 RCC cases and 1192 controls enrolled in a hospital-based case-control study conducted in Central and Eastern Europe. Overall associations with RCC risk were not observed; however, subgroup analyses revealed associations after stratification by median age of diagnosis and family history of cancer. Among subjects over 60 yr, reduced risks were observed among carriers of the f alleles in the FokI single-nuceotide polymorphism (SNP) (odds ratio [OR] = 0.61 for Ff and OR = 0.74 for ff genotypes) compared to subjects with the FF genotype (P trend = 0.04; P interaction = 0.004). Subjects with the BB BsmI genotype and a positive family history of cancer had lower risk compared to subjects with the bb allele (OR = 0.60; 95% CI: 0.33-1.1; P trend = 0.05). Genotype associations with these subgroups were not modified when dietary sources of vitamin D or calcium were considered. Additional studies of genetic variation in the VDR gene are warranted. Copyright \ua9 Taylor & Francis Group, LLC