F. Costa Mira

Global DNA hypomethylation occurs in the early stages of intestinal type gastric carcinoma.

BACKGROUND: Global DNA hypomethylation has been found in the premalignant stages of some neoplasms and has been implicated as an important factor for tumour progression. AIMS: The aim of this study was to evaluate whether DNA hypomethylation occurs during the process of gastric carcinogenesis. METHODS: Gastric specimens were obtained from 49 patients and histologically classified as: normal 10, superficial gastritis 14, chronic atrophic gastritis with intestinal metaplasia 15, and intestinal type of gastric carcinoma 10. Global DNA methylation was assessed by incubating DNA with (3H)-S-adenosylmethionine and Sss1 methylase. A higher incorporation of (3H) methyl groups reflects a lower degree of intrinsic methylation. RESULTS: A graduated increase in (3H) methyl group incorporation into DNA was found over the range extending from normal gastric mucosa, to superficial gastritis and to chronic atrophic gastritis (136,556 (24,085) v 235,725 (38,636) v 400,998 (26,747 dpm/micrograms/DNA respectively; p = 0.0002). No further increase was found in specimens from patients with carcinoma. No differences were found between extent of DNA methylation in neoplastic or non-neoplastic mucosa from patients with gastric carcinoma. Hypomethylation of DNA increased substantially with severe atrophy (p = 0.01) or with type III intestinal metaplasia (p = 0.15). CONCLUSIONS: Global DNA hypomethylation occurs in the early stages of gastric carcinogenesis, and it may be a novel biomarker of gastric neoplasia, useful in monitoring the response to chemopreventive agents.

Effect of folate supplementation on DNA methylation of rectal mucosa in patients with colonic adenomas: correlation with nutrient intake

We have evaluated the effect of folate supplementation (5 mg/day) on global deoxyribonucleic acid (DNA) methylation status of the rectal mucosa of 20 patients with resected colonic adenomas in a prospective, controlled, cross-over study. Baseline values of DNA methylation were inversely correlated with caloric (P = 0.03) and fat intake (P = 0.05) and patients harbouring multiple polyps consumed significantly more calories (P = 0.0006), fat (P = 0.009) and carbohydrates (P = 0.009) as compared to patients having one single lesion. Folate supplementation resulted in a significant decrease of DNA hypomethylation in 7/20 patients (P = 0.05) which returned to previous values after placebo treatment. This effect was significantly correlated with number of polyps, with all the responders presenting one single lesion, whereas 8/13 of the non-responders had multiple ones (chi2 = 7.17, P = 0.007). In conclusion, folate supplementation may decrease degree of DNA hypomethylation, but only in patients with one single polyp. In those with multiple lesions, other nutritional factors such as caloric and fat intake, may be more determinant.

DNA hypomethylation and proliferative activity are increased in the rectal mucosa of patients with long-standing ulcerative colitis

DNA methylation and DNA cytometric parameters were evaluated in the rectal mucosa from patients with extensive and long‐standing ulcerative colitis.

The muir-torre syndrome: a rare variant of hereditary nonpolyposis colorectal cancer associated with hmsh2 mutation

The Muir-Torre syndrome is a rare autosomal dominant disorder characterized by the association of visceral malignancies with typical skin lesions. This syndrome is now considered a subtype of the more common hereditary nonpolyposis colorectal cancer syndrome (HNPCC). This last condition has been ascribed to mutations in four mismatch repair genes, and similar mutations, mostly located at hMSH2 gene, are now being described in some Muir-Torre patients. We describe the case of a 64-yr-old woman with no family history of colorectal cancer, who developed two visceral malignancies belonging to the usual spectrum of hereditary nonpolyposis colorectal cancer (colon and stomach), beginning at age 41. She additionally developed several skin tumors, including multiple keratoacanthomas, thus fulfilling Muir-Torre diagnostic criteria. Because of her cutaneous phenotype, she was screened for DNA mismatch repair gene mutations by in vitro synthetized protein assay (IVSP) and a truncating mutation was identified at hMSH2. We further discuss the clinical significance of the Muir-Torre phenotype, the association of this syndrome with hMSH2 mutations and the important implications of genetic diagnosis for the patient and her offspring.

Folate status, DNA methylation and colon cancer risk in inflammatory bowel disease

*Servi¢os de Gastrenterologia e Laborat6rio de Biologia Molecular ~Servi¢o de Patologia Morfol6gica, Instituto Portugu#s de Oncologia Francisco Gentil, Lisboa Portugal, tServi¢o Universit~rio de Medicina Interna e de Gastrenterologia e do Hospital Pulido Valente, Portugal (Correspondence to MC, Servigo de Gastrenterologia, Instituto Portugu#s de Oncologia Francisco Gentil, Rua Prof. Lima Basto, 1093 Lisboa Codex, Portugal)

DNA methylation and subclinical vitamin deficiency of folate, pyridoxal-phosphate and vitamin B12 in chronic alcoholics

Alcohol abuse is known to adversely affect folate, vitamin B12 and pyridoxal-phosphate metabolism, which are required for de novo synthesis of methionine. Methionine is the precursor of S-adenosylmethionine, the principal methylating agent in the organism, including DNA. The objective of this study was to measure DNA methylation in peripheral lymphocytes and the circulating concentrations of these three vitamins in chronic alcoholics. DNA methylation was assessed by measuring DNA methyl accepting capacity in the presence of Ssauthor methylase. Serum pyridoxal-phosphate and red blood cell folate concentrations were significantly depressed in alcoholics (P<0.0001 and P=0.02, respectively). DNA from patients who consumed 3.0 g/ethanol/kg/day or more, incorporated significantly more (3H) methyl groups, which reflects a lower state of intrinsic methylation (P=0.01). DNA hypomethylation was also more pronounced in malnourished alcoholics (P=0.03). We conclude that heavy ethanol consumption is associated with folate and vitamin B6 depletion, which may interfere with DNA methylation status by impairing de novo methionine synthesis.