Gastroenterology

Gastroenterology

Volume 134, Issue 1, January 2008, Pages 47-55
Gastroenterology

Clinical–Alimentary Tract
Genomic Methylation of Leukocyte DNA in Relation to Colorectal Adenoma Among Asymptomatic Women

https://doi.org/10.1053/j.gastro.2007.10.013Get rights and content

Background & Aims: Systemic inhibition of DNA methylation causes cancers in animals, in part by inducing genetic instability. Epidemiologic evidence linking low genomic methylation in systemic blood DNA to carcinogenesis is limited, however, specifically to the colorectum, in which genetic instability is a primary etiologic factor. We examined genomic methylation of leukocyte DNA in relation to colorectal adenoma (CRA) among asymptomatic women (40–79 years of age) participating in a multicenter colonoscopy screening study (CONCeRN Study, 2000–2002). Methods: Of all participants who completed self-administered risk factor and food frequency questionnaires, peripheral blood donation, and colonoscopy, 115 pairs of CRA cases and controls with matching age and month of blood draw were studied. Genomic methylation of leukocyte DNA was determined by liquid chromatography mass spectrometry. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Results: Compared with women in the lowest tertile of genomic methylation, women in the second (OR, 0.72; 95% CI: 0.34–1.52) and third tertiles (OR, 0.17; 95% CI: 0.06–0.49) had lower risk of CRA (P trend = .002). The inverse relationship was stronger for nonadvanced than for advanced adenoma and, less notably, for proximal than for distal adenoma. The association was also moderately more protective with low rather than high total folate intake but did not differ by other nutrients involved in 1-carbon metabolism or colorectal cancer risk factors. Conclusions: Our findings regarding asymptomatic CRA implicate systemic genomic methylation as a potential etiologic factor for an early stage of CRA.

Section snippets

The Colorectal Neoplasia Screening With Colonoscopy in Asymptomatic Women at Regional Navy/Army Medical Centers Study

The Colorectal Neoplasia Screening With Colonoscopy in Asymptomatic Women at Regional Navy/Army Medical Centers (CONCeRN) Study is a colonoscopy screening study with a primary objective to determine the efficacy of colonoscopy vs sigmoidoscopy as a screening tool for colorectal neoplasia, as described in detail elsewhere.17 Subjects were recruited between July 1999 and December 2002 among consecutive female patients at 4 medical centers (National Naval Medical Center, Bethesda, MD; Walter Reed

Results

Compared with controls, cases were more likely to have never used postmenopausal hormone replacement therapy, more likely to have smoked for greater than 20 years, and more likely to have consumed more of the selected red meats and processed meat (Table 1). Otherwise, cases did not significantly differ from controls with respect to demographics, study centers, colorectal cancer risk factors, and known determinants of 1-carbon metabolism.

Percent genomic methylation of leukocyte DNA was

Discussion

Our finding of an inverse relationship between systemic genomic methylation and CRA is consistent with a previous case-control study8 and demonstrates a dose response. Compared with the highest tertile of genomic methylation, our finding is equivalent to ORs of 4.2 (95% CI: 1.5–11.8) for the middle tertile and 5.8 (95% CI: 2.0–16.6) for the lowest tertile, whereas the ORs were 6.68 (95% CI: 0.99–45.12) and 10.27 (95% CI: 2.05–51.46), respectively, in the previous study of 35 adenoma patients

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  • Cited by (0)

    Supported by the Intramural Research Program of the National Institutes of Health at the National Cancer Institute (to U.L.), by K07-CA108910-01A1 from the National Cancer Institute (to A.F.), and by research grants from the American College of Gastroenterology and the American Society for Gastrointestinal Endoscopy.

    The authors thank the following investigators for participation in the CONCeRN Study: Drs J. Butler, P. Perdue, and P.J. Chandler, Bethesda, Maryland; Dr C. Furlong, Portsmouth, Virginia; and Drs J. Shad and R. Schindler, San Diego, California; Mary K. Keyes at Tufts University for assistance with assays; Shelley Niwa and Mark Stewart at Westat and Jane Curtin at the Information Management Services, Inc for computer support; Janis Koci at Frederick repository for biospecimen handling; Dr Amy F. Subar for advice on dietary assessment; Dr Tom Fears for assistance in quality control analysis; Drs Bill Kopp and Wen Shao at SAIC-Frederick for processing quality control samples; and Tawanda Roy at Nutritional Epidemiology Branch for research assistance.

    Conflicts of interest: No conflicts of interest exist.

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