Epithelial cancers in the post-genomic era: should we reconsider our lifestyle?

The age-related epithelial cancers of the breast, colorectum and prostate are the most prevalent and are increasing in our aging populations. Epithelial cells turnover rapidly and mutations naturally accumulate throughout life. Most epithelial cancers arise from this normal mutation rate. All elderly individuals will harbour many cells with the requisite mutations and most will develop occult neoplastic lesions. Although essential for initiation, these mutations are not sufficient for the progression of cancer to a life-threatening disease. This progression appears to be dependent on context: the tissue ecosystem within individuals and lifestyle exposures across populations of individuals. Together, this implies that the seeds may be plentiful but they only germinate in the right soil. The incidence of these cancers is much lower in Eastern countries but is increasing with Westernisation and increases more acutely in migrants to the West. A Western lifestyle is strongly associated with perturbed metabolism, as evidenced by the epidemics of obesity and diabetes: this may also provide the setting enabling the progression of epithelial cancers. Epidemiology has indicated that metabolic biomarkers are prospectively associated with cancer incidence and prognosis. Furthermore, within cancer research, there has been a rediscovery that a switch in cell metabolism is critical for cancer progression but this is set within the metabolic status of the host. The seed may only germinate if the soil is fertile. This perspective brings together the different avenues of investigation implicating the role that metabolism may play within the context of post-genomic concepts of cancer

Tissue specific DNA methylation of CpG islands in normal human adult somatic tissues distinguishes neural from non-neural tissues

Although most CpG islands are generally thought to remain unmethylated in all adult somatic tissues, recent genome-wide approaches have found that some CpG islands have distinct methylation patterns in various tissues, with most differences being seen between germ cells and somatic tissues. Few studies have addressed this among human somatic tissues and fewer still have studied the same sets of tissues from multiple individuals. In the current study, we used Restriction Landmark Genomic Scanning to study tissue specific methylation patterns in a set of 12 human tissues collected from multiple individuals. We identified 34 differentially methylated CpG islands among these tissues, many of which showed consistent patterns in multiple individuals. Of particular interest were striking differences in CpG island methylation, not only among brain regions, but also between white and grey matter of the same region. These findings were confirmed for selected loci by quantitative bisulfite sequencing. Cluster analysis of the RLGS data indicated that several tissues clustered together, but the strongest clustering was in brain. Tissues from different brain regions clustered together, and, as a group, brain tissues were distinct from either mesoderm or endoderm derived tissues which demonstrated limited clustering. These data demonstrate consistent tissue specific methylation for certain CpG islands, with clear differences between white and grey matter of the brain. Furthermore, there was an overall pattern of tissue specifically methylated CpG islands that distinguished neural tissues from non-neural

β-adrenergic receptor antagonists and fracture risk : a meta-analysis of selectivity, gender, and site-specific effects

Summary By meta-analysis, the risk of fracture was 15 % lower in patients treated with β-adrenergic blockers compared to controls independent of gender, fracture site, and dose. This might be attributable to β1-selective blockers. Introduction The aim of this study is to determine by meta-analysis whether β-adrenergic blockers (BBs) reduce fracture risk and whether the effect, if demonstrable, is dependent upon selectivity, dose, gender, or fracture site. Methods A literature search was performed in electronic databases MEDLINE, EMBASE, and reference sections of relevant articles to identify eligible studies. Adjusted estimates of fracture risk effect size (ES) were pooled across studies using fixed or random-effects (RE) meta-analysis as appropriate. Dose-related effects were evaluated using meta-regression. To explore the relative efficacy of β1-selective blockers in comparison to nonselective BBs, adjusted indirect comparison was performed. Results A total of 16 studies (7 cohort and 9 case–control studies), involving 1,644,570 subjects, were identified. The risk of any fracture was found to be significantly reduced in subjects receiving BBs as compared to control subjects (16 studies, RE pooled ES = 0.86, 95 % CI 0.78–0.93; I2 = 87 %). In a sensitivity analysis limited to those studies deemed to be most robust, the BB effect to reduce fracture risk was sustained (four studies, pooled ES = 0.79, 95 % CI 0.67–0.94; I2 = 96 %). The risk of a hip fracture was lower in both women and men receiving BBs (women: pooled ES = 0.86, 95 % CI 0.80–0.91; I2 = 1 % and men: pooled ES = 0.80, 95 % CI 0.71–0.90; I2 = 0 %). Similar risk reductions were found for clinical vertebral and forearm fractures, although statistical significance was not reached. The reduction in risk did not appear to be dose-related (test for a linear trend p value 0.150). Using adjusted indirect comparisons, it was estimated that β1-selective agents were significantly more effective than nonselective BBs in reducing the risk of any fracture (six studies, β1-selective blockers vs. nonselective BBs: RE pooled ES = 0.82, 95 % CI = 0.69–0.97). Conclusions The findings suggest that the risk of fracture is approximately 15 % lower in patients treated with BBs compared to controls independent of gender, fracture site, and dose. This risk reduction might be associated with the effects of β1-selective blockers