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Quantitative Analysis of Plasma TP53 249^Ser-Mutated DNA by Electrospray Ionization Mass Spectrometry

¹ IARC, Lyon, France; Departments of ² Epidemiology and ³ Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland; ⁴ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland; ⁵ Medical Research Council, Banjul, The Gambia; and ⁶ Department of Genetic Alterations in Carcinogenesis, German Cancer Research Center (Deutches Krebsforshungszentrum), Heidelberg, Germany

Requests for reprints: Marlin D. Friesen, Johns Hopkins Bloomberg School of Public Health, Department of Environmental Health Sciences, 615 North Wolfe Street, Room E7032, Baltimore, MD 21205. Phone: 410-955-4235; Fax: 410-955-0617. E-mail: mfriesen{at}jhsph.edu

A mutation in codon 249 of the TP53 gene (249^Ser), related to aflatoxin B₁ exposure, has previously been associated with hepatocellular carcinoma risk. Using a novel internal standard plasmid, plasma concentrations of 249^Ser-mutated DNA were quantified by electrospray ionization mass spectrometry in 89 hepatocellular carcinoma cases, 42 cirrhotic patients, and 131 nonliver diseased control subjects, all from highly aflatoxin-exposed regions of The Gambia. The hepatocellular carcinoma cases had higher median plasma concentrations of 249^Ser (2,800 copies/mL; interquartile range: 500-11,000) compared with either cirrhotic (500 copies/mL; interquartile range: 500-2,600) or control subjects (500 copies/mL; interquartile range: 500-2,000; P < 0.05). About half (52%) of the hepatocellular carcinoma cases had >2,500 copies of 249^Ser/mL plasma, corresponding to the prevalence of this mutation in liver tumors in The Gambia. In comparison, only 15% of control group and 26% of cirrhotic participants exceeded this level (P < 0.05). Further subset analysis revealed a statistically significant, quantitative relation between diagnosis of hepatocellular carcinoma and levels of 249^Ser detected at 2,501 to 10,000 copies/mL plasma (odds ratio, 3.8; 95% confidence interval, 1.3-10.9) and at >10,000 copies/mL plasma (odds ratio, 62; 95% confidence interval, 4.7-820) when compared with control subjects and after adjusting for age, gender, recruitment site, hepatitis B and C serologic status, and total DNA concentration. Levels of >10,000 copies of 249^Ser/mL plasma were also significantly associated with the diagnosis of hepatocellular carcinoma (odds ratio, 15; 95% confidence interval, 1.6-140) when compared with cirrhotic patients. Potential applications for the quantification of 249^Ser DNA in plasma include estimation of long-term, cumulative aflatoxin exposure and selection of appropriate high-risk individuals for targeted intervention. (Cancer Epidemiol Biomarkers Prev 2005;14(12):2956–62)

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