Association of leukocyte DNA methylation changes with dietary folate and alcohol intake in the EPIC study.

BACKGROUND: There is increasing evidence that folate, an important component of one-carbon metabolism, modulates the epigenome. Alcohol, which can disrupt folate absorption, is also known to affect the epigenome. We investigated the association of dietary folate and alcohol intake on leukocyte DNA methylation levels in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Leukocyte genome-wide DNA methylation profiles on approximately 450,000 CpG sites were acquired with Illumina HumanMethylation 450K BeadChip measured among 450 women control participants of a case-control study on breast cancer nested within the EPIC cohort. After data preprocessing using surrogate variable analysis to reduce systematic variation, associations of DNA methylation with dietary folate and alcohol intake, assessed with dietary questionnaires, were investigated using CpG site-specific linear models. Specific regions of the methylome were explored using differentially methylated region (DMR) analysis and fused lasso (FL) regressions. The DMR analysis combined results from the feature-specific analysis for a specific chromosome and using distances between features as weights whereas FL regression combined two penalties to encourage sparsity of single features and the difference between two consecutive features. RESULTS: After correction for multiple testing, intake of dietary folate was not associated with methylation level at any DNA methylation site, while weak associations were observed between alcohol intake and methylation level at CpG sites cg03199996 and cg07382687, with qval = 0.029 and qval = 0.048, respectively. Interestingly, the DMR analysis revealed a total of 24 and 90 regions associated with dietary folate and alcohol, respectively. For alcohol intake, 6 of the 15 most significant DMRs were identified through FL. CONCLUSIONS: Alcohol intake was associated with methylation levels at two CpG sites. Evidence from DMR and FL analyses indicated that dietary folate and alcohol intake may be associated with genomic regions with tumor suppressor activity such as the GSDMD and HOXA5 genes. These results were in line with the hypothesis that epigenetic mechanisms play a role in the association between folate and alcohol, although further studies are warranted to clarify the importance of these mechanisms in cancer.

Circulating plasma phospholipid fatty acids and risk of pancreatic cancer in a large European cohort.

There are both limited and conflicting data on the role of dietary fat and specific fatty acids in the development of pancreatic cancer. In this study, we investigated the association between plasma phospholipid fatty acids and pancreatic cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. The fatty acid composition was measured by gas chromatography in plasma samples collected at recruitment from375 incident pancreatic cancer cases and375 matched controls. Associations of specific fatty acids with pancreatic cancer risk were evaluated using multivariable conditional logistic regression models with adjustment for established pancreatic cancer risk factors. Statistically significant inverse associations were found between pancreatic cancer incidence and levels of heptadecanoic acid (ORT3-T1 [odds ratio for highest versus lowest tertile] =0.63; 95%CI[confidence interval] = 0.41-0.98; ptrend = 0.036), n-3 polyunsaturated α-linolenic acid (ORT3-T1 = 0.60; 95%CI = 0.39-0.92; ptrend = 0.02) and docosapentaenoic acid (ORT3-T1 = 0.52; 95%CI = 0.32-0.85; ptrend = 0.008). Industrial trans-fatty acids were positively associated with pancreatic cancer risk among men (ORT3-T1 = 3.00; 95%CI = 1.13-7.99; ptrend = 0.029), while conjugated linoleic acids were inversely related to pancreatic cancer among women only (ORT3-T1 = 0.37; 95%CI = 0.17-0.81; ptrend = 0.008). Among current smokers, the long-chain n-6/n-3 polyunsaturated fatty acids ratio was positively associated with pancreatic cancer risk (ORT3-T1 = 3.40; 95%CI = 1.39-8.34; ptrend = 0.007). Results were robust to a range of sensitivity analyses. Our findings suggest that higher circulating levels of saturated fatty acids with an odd number of carbon atoms and n-3 polyunsaturated fatty acids may be related to lower risk of pancreatic cancer. The influence of some fatty acids on the development of pancreatic cancer may be sex-specific and modulated by smoking.

Biomarkers of folate and vitamin B12 and breast cancer risk: report from the EPIC cohort.

Epidemiological studies have reported inconsistent findings for the association between B vitamins and breast cancer (BC) risk. We investigated the relationship between biomarkers of folate and vitamin B12 and the risk of BC in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Plasma concentrations of folate and vitamin B12 were determined in 2,491 BC cases individually matched to 2,521 controls among women who provided baseline blood samples. Multivariable logistic regression models were used to estimate odds ratios by quartiles of either plasma B vitamin. Subgroup analyses by menopausal status, hormone receptor status of breast tumors (estrogen receptor [ER], progesterone receptor [PR] and human epidermal growth factor receptor 2 [HER2]), alcohol intake and MTHFR polymorphisms (677C > T and 1298A > C) were also performed. Plasma levels of folate and vitamin B12 were not significantly associated with the overall risk of BC or by hormone receptor status. A marginally positive association was found between vitamin B12 status and BC risk in women consuming above the median level of alcohol (ORQ4-Q1 = 1.26; 95% CI 1.00-1.58; Ptrend = 0.05). Vitamin B12 status was also positively associated with BC risk in women with plasma folate levels below the median value (ORQ4-Q1 = 1.29; 95% CI 1.02-1.62; Ptrend = 0.03). Overall, folate and vitamin B12 status was not clearly associated with BC risk in this prospective cohort study. However, potential interactions between vitamin B12 and alcohol or folate on the risk of BC deserve further investigation.

Heterogeneity, Cell Biology and Tissue Mechanics of Pseudostratified Epithelia: Coordination of Cell Divisions and Growth in Tightly Packed Tissues.

Pseudostratified epithelia (PSE) are tightly packed proliferative tissues that are important precursors of the development of diverse organs in a plethora of species, invertebrate and vertebrate. PSE consist of elongated epithelial cells that are attached to the apical and basal side of the tissue. The nuclei of these cells undergo interkinetic nuclear migration (IKNM) which leads to all mitotic events taking place at the apical surface of the epithelium. In this review, we discuss the intricacies of proliferation in PSE, considering cell biological, as well as the physical aspects. First, we summarize the principles governing the invariability of apical nuclear migration and apical cell division as well as the importance of apical mitoses for tissue proliferation. Then, we focus on the mechanical and structural features of these tissues. Here, we discuss how the overall architecture of pseudostratified tissues changes with increased cell packing. Lastly, we consider possible mechanical cues resulting from these changes and their potential influence on cell proliferation.

Analysis of K-ras codon 12 and TP53 mutations in patients with advanced colorectal carcinoma.

BACKGROUND: Colorectal cancer (CRC) is one of the most common types of cancer, affecting 3 - 5% of the global population. K-ras protooncogene and TP53 tumour suppressor gene mutations are among the most common genetic alterations detected in advanced colorectal tumours. OBJECTIVE: To investigate the role of K-ras codon 12 and TP53 exons 5 - 9 mutations in late-stage CRC patients. METHODS: Blood samples were collected from 249 CRC patients, of whom 147 presented with advanced carcinoma. K-ras codon 12 mutations were analysed using polymerase chain reaction-restriction fragment length polymorphism, while direct sequencing was used in screening for TP53 exons 5 - 9 mutations. RESULTS: No significant changes were observed in TP53 exons 5 - 9, except for two cases in which nucleotide replacements were observed in the non-coding regions in intron 4 (c.376-19C>T) and intron 9 (c.993+12T>C). Heterozygous mutations in K-ras codon 12 were observed in 79 individuals suffering from advanced CRC (53.7%). Colon and rectal tumours were equally distributed among the heterozygotes, but colon tumours were mostly present in wild-type homozygotes (84.6%). There was also a predominance of Caucasians among heterozygotes and a predominance of Asians among the wild-type homozygotes. CONCLUSION: Analysis of peripheral blood samples of CRC patients suffering from advanced carcinoma has prognostic value only for K-ras codon 12 mutations, and not for TP53 mutations.

Comparison of the postoperative fibrinogen, alpha-1-antitrypsin and alpha-2- macroglobulin concentrations in the blood of wounded soldiers of Croatian Army and peacetime injured civilians.

In 10 wounded Croatian Army soldiers and in 10 civilians with accidental musculosceletal traumatisation, blood concentrations of the 3 acute phase proteins: fibrinogen, alpha-1-antitrypsin and alpha-2-macroglobulin on the 1st, 5th and 10th postoperative day were assessed. On the 5th day after injury, increased concentrations of all 3 acute phase proteins (APP) were found in all patients. The rise of the fibrinogen concentrations in the wounded soldiers was the steepest. On the 10th day after wounding, fibrinogen concentrations in the gorup of wounded soldiers were significantly lower than those in the group of injured civilians. On the 10th day after wounding there were no differences between the 2 groups in the concentrations of alpha-1-antitrypsin and of alpha-2-macroglobulin. The lower fibrinogen concentrations in the wounded soldiers could be explained by the modulation of the general reactivity of the organism to injury, proposed by Woloski, which is induced by stress and microtrauma on battlefield before the wounding.