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TP53 and KRAS2 Mutations in Plasma DNA of Healthy Subjects and Subsequent Cancer Occurrence: A Prospective Study

¹ IARC; ² Université Catholique de Lyon, Lyon, France; ³ Imperial College London and University of Torino; ⁴ ISI Foundation; ⁵ University of Torino, Turin, Italy; ⁶ Cancer Risk Factor Branch, Molecular Biology Laboratory, and ⁷ Molecular and Nutritional Epidemiology Unit, CSPO-Scientific Institute of Tuscany, Firenze, Italy; ⁸ Genetics Research Institute; ⁹ Istituto di Ricerche Farmacologiche Mario Negri; ¹⁰ Department of Epidemiology, National Cancer Istitute, Milan, Italy; ¹¹ Department of Occupational and Environmental Medicine; ¹² Department of Clinical Epidemiology, Åalborg Hospital and Åarhus University Hospital, and Department of Epidemiology and Social Medicine, University of Åarhus, Aarhus, Denmark; ¹³ Department of Oncology, University of Cambridge; ¹⁴ Medical Research Council Dunn Human Nutrition Unit, Cambridge, United Kingdom; ¹⁵ Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark; ¹⁶ Institute of Community Medicine, University of Tromso, Tromso, Norway; ¹⁷ Institut National de la Santé et de la Recherche Médicale U521, Institut Gustave Roussy, Villejuif, France; ¹⁸ German Institute of Human Nutrition, Potsdam-Rehbücke, Germany; ¹⁹ Department of Hygiene and Epidemiology, University of Athens Medical School, Athens, Greece; ²⁰ Ragusa Cancer Registry, Azienda Ospedaliera Civile MP Arezzo, Ragusa, Italy; ²¹ Dipartimento di Medicina Clinica e Sperimentale, Università Federico II, Naples, Italy; ²² Center for Nutrition and Health, National Institute for Public Health and the Environment, Bilthoven, the Netherlands; ²³ Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht, the Netherlands; ²⁴ Department of Epidemiology, Catalan Institute of Oncology, Barcelona, Spain; ²⁵ Andalusian School of Public Health, Granada, Spain; ²⁶ Department of Public Health of Guipuzkoa, San Sebastian, Spain; ²⁷ Public Health Institute, Navarra, Spain; ²⁸ Epidemiology Department, Murcia Health Council, Murcia, Spain; ²⁹ Dirección General de Salud Pública, Consejería de Salud y Servicios Sanitarios Asturias, Oviedo, Spain; ³⁰ Department of Public Health and Clinical Medicine, Umeå University, Umea, Sweden; and ³¹ Cancer Research UK Epidemiology Unit, University of Oxford, United Kingdom

Requests for reprints: Pierre Hainaut, IARC, 150 Cours Albert Thomas, 69372 Lyon Cedex 08, France. Phone: 33-4-72-73-85-32; Fax: 33-4-72-73-83-22; E-mail: hainaut{at}iarc.fr.

In cancer patients, plasma often contains mutant DNA released by cancer cells. We have assessed the significance of plasma DNA mutations for subsequent cancer development in healthy subjects in a large longitudinal prospective study. The European Prospective Investigation into Cancer and Nutrition study was analyzed with a nested case-control design. Cases were nonsmokers or ex-smokers for >10 years and newly diagnosed with lung, bladder, or upper aerodigestive tract cancers or leukemia accrued after a median follow-up of 6.3 years. Controls were matched 2:1 for follow-up, age, sex, area of recruitment, and smoking status. KRAS2 mutations were detected by mutant-enriched PCR and sequencing (n = 1,098). TP53 mutations were detected by denaturing high-performance liquid chromatography, temporal temperature gradient electrophoresis, and sequencing (n = 550). KRAS2 or TP53 mutations were detected in 13 of 1,098 (1.2%) and 20 of 550 (3.6%) subjects, respectively, 16 of whom developed cancer on average after 18.3 months of follow-up. Among 137 subjects who developed bladder cancer, 5 had KRAS2 mutations [odds ratio (OR), 4.25; 95% confidence interval (95% CI), 1.27-14.15] and 7 had TP53 mutations (OR, 1.81; 95% CI, 0.66-4.97). There was a nonsignificant trend for association between TP53 mutations and bulky adducts in lymphocyte DNA (OR, 2.78; 95% CI, 0.64-12.17). This is the first report of TP53 or KRAS2 mutations in the plasma of healthy subjects in a prospective study, suggesting that KRAS2 mutation is detectable ahead of bladder cancer diagnosis. TP53 mutation may be associated with environmental exposures. These observations have implications for monitoring early steps of carcinogenesis. (Cancer Res 2006; 66(13): 6871-6)

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