Association between Folate Levels and CpG Island Hypermethylation in Normal Colorectal Mucosa

Folate exists as functionally diverse species within cells. Although folate deficiency may contribute to DNA hypomethylation in colorectal cancer, findings on the association between total folate concentration and global DNA methylation have been inconsistent. This study determined global, LINE-1, and Alu DNA methylation in blood and colon of healthy and colorectal cancer patients and their relationship to folate distribution. Blood and normal mucosa from 112 colorectal cancer patients and 114 healthy people were analyzed for global DNA methylation and folate species distribution using liquid chromatography tandem mass spectrometry. Repeat element methylation was determined using end-specific PCR. Colorectal mucosa had lower global and repeat element DNA methylation compared with peripheral blood (P < 0.0001). After adjusting for age, sex and smoking history, global but not repeat element methylation was marginally higher in normal mucosa from colorectal cancer patients compared with healthy individuals. Colorectal mucosa from colorectal cancer subjects had lower 5-methyltetrahydrofolate and higher tetrahydrofolate and formyltetrahydrofolate levels than blood from the same individual. Blood folate levels should not be used as a surrogate for the levels in colorectal mucosa because there are marked differences in folate species distribution between the two tissues. Similarly, repeat element methylation is not a good surrogate measure of global DNA methylation in both blood and colonic mucosa. There was no evidence that mucosal global DNA methylation or folate distribution was related to the presence of cancer per se, suggesting that if abnormalities exist, they are confined to individual cells rather than the entire colon. Cancer Prev Res; 5(7);

Section: Discussionmentioning

confidence: 99%

Relative Distribution of Folate Species Is Associated with Global DNA Methylation in Human Colorectal Mucosa

Liu

Hesson

Meagher

et al. 2012

“…Taking into consideration both measured and unmeasured risk factors/genetic susceptibilities, molecular information derived from histologically normal mucosae has been extensively investigated, such as the field effects of oral leukoplakia, Barrett's esophagus (39), and colon neoplasm (40,41). Mutations of p53 or p53 oncoprotein are relatively late events in carcinogenesis (42,43), so, despite their biological plausibility as cancer predictors, they are insufficient for risk assessments for SCC in the UADT.…”

Section: Discussionmentioning

confidence: 99%

Revisit of Field Cancerization in Squamous Cell Carcinoma of Upper Aerodigestive Tract: Better Risk Assessment with Epigenetic Markers

Lee

Wang

et al. 2011

We quantified field cancerization of squamous cell carcinoma in the upper aerodigestive tract with epigenetic markers and evaluated their performance for risk assessment. Methylation levels were analyzed by quantitative methylation-specific PCR of biopsied specimens from a training set of 255 patients and a validation set of 224 patients. We also measured traditional risk factors based on demographics, lifestyle, serology, genetic polymorphisms, and endoscopy. The methylation levels of four markers increased stepwise, with the lowest levels in normal esophageal mucosae from healthy subjects without carcinogen exposure, then normal mucosae from healthy subjects with carcinogen exposure, then normal mucosae from cancer patients, and the highest levels were in cancerous mucosae (P < 0.05). Cumulative exposure to alcohol increased methylation of homeobox A9 in normal mucosae (P < 0.01). Drinkers had higher methylation of ubiquitin carboxyl-terminal esterase L1 and metallothionein 1M (P < 0.05), and users of betel quid had higher methylation of homeobox A9 (P ¼ 0.01). Smokers had increased methylation of all four markers (P < 0.05). Traditional risk factors allowed us to discriminate between patients with and without cancers with 74% sensitivity (95% CI: 67%-81%), 74% specificity (66%-82%), and 80% area under the curve (67%-91%); epigenetic markers in normal esophageal mucosa had values of 74% (69%-79%), 75% (67%-83%), and 83% (79%-87%); and both together had values of 82% (76%-88%), 81% (74%-88%), and 91% (88%-94%). Epigenetic markers done well in the validation set with 80% area under the curve (73%-85%). We concluded that epigenetics could improve the accuracies of risk assessment.

“…Folate supplementation has come under fire recently, with some studies raising safety concerns by showing an association with an increased incidence of and/or mortality from various cancers (18). Furthermore, laboratory research has linked high levels of folate with accelerated age-related DNA methylation (19), leading one to wonder whether diet could have had an influence on the constitutional methylation as reported by Wong et al (3). Indeed, folate (and diet in general) may be just the tip of an iceberg of epigenetic modulators.…”

mentioning

confidence: 99%

Time to Think Outside the (Genetic) Box

Issa

Garber

2011

Many patients develop cancers that have clinical features of inherited syndromes (e.g., young age of onset and unique pathology) but lack mutations in the genes characteristic of the disease. In this issue of the journal, Wong et al. report that somatic epigenetic inactivation could explain some such cases in the setting of BRCA1-associated breast cancer. Here, we discuss the implications of this work in terms of the etiology, risk, and potential prevention of cancer. Cancer Prev Res; 4(1); 6-8. Ó2011 AACR.Identification of high-risk populations is a research priority in cancer prevention. Genetic predisposition to cancer development is an obvious marker for risk, and several interventions have been shown to reduce cancer mortality in this group of patients. It remains puzzling, however, that despite more than 2 decades of research into mutations in the genes most commonly responsible for inherited cancer, such mutations are not found in a large number of cases that share clinical criteria for having inherited cancer (young age at onset, specific pathology, etc.; ref. 1). For many years, this absence of mutations was easy to explain away-our knowledge of cancer genetics was thought to be fragmentary, and these puzzling cases were assumed to carry mutations in genes yet to be identified. However, large-scale sequencing efforts in major human malignancies such as colorectal cancer (2) have not uncovered previously unknown high-frequency mutations. We are left, therefore, with the somewhat unsatisfying hypothesis that rare mutations in multiple genes or a combination of alterations in several genes that act collectively underlie the many cases of inherited cancer with no known cancerassociated mutation.In this issue of the journal, Wong et al. (3) present data supporting an alternative concept: that is, constitutional epigenetic defects can account for a significant proportion of cancers with the clinical/pathologic features but not the characteristic mutations of inherited cancers. This study was conducted in 255 female breast cancer patients without an identified germline BRCA1 (or BRCA2) mutation and 169 age-matched female controls. The breast cancers in the cases were required to share certain features of inherited BRCA1-associated disease [onset at a young patient age (<40 years), and aggressive pathology). The patients were assessed for 9 tumor pathology features deemed to be characteristic of cancers in BRCA1 mutation carriers and then were divided into 3 groups, as follows: 5 or more characteristic features (group 1), 4 features (group 2), and 3 or fewer features (group 3). Thirty-one percent of the patients with the most BRCA1-like tumors (group 1) had detectable BRCA1 methylation in peripheral bloodderived DNA, and the cancers themselves had high levels of BRCA1 methylation. The frequency of peripheral blood BRCA1 methylation was much lower (5%) in patients whose cancers had fewer BRCA1 features (group 3), and the non-BRCA1-like cancers themselves had low levels of BRCA1 methylation. There was an ...