title: TP53 and KRAS2 mutations in plasma DNA of healthy subjects and subsequent cancer occurrence: a prospective study.
abstract: 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.
authors.affiliation: IARC, 150 Cours Albert Thomas, 69372 Lyon Cedex 08, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Gormally
authors.forename: Paolo
authors.initials: P
authors.lastname: Vineis
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Matullo
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Veglia
authors.forename: Elodie
authors.initials: E
authors.lastname: Caboux
authors.forename: Emilie
authors.initials: E
authors.lastname: Le Roux
authors.forename: Marco
authors.initials: M
authors.lastname: Peluso
authors.forename: Seymour
authors.initials: S
authors.lastname: Garte
authors.forename: Simonetta
authors.initials: S
authors.lastname: Guarrera
authors.forename: Armelle
authors.initials: A
authors.lastname: Munnia
authors.forename: Luisa
authors.initials: L
authors.lastname: Airoldi
authors.forename: Herman
authors.initials: H
authors.lastname: Autrup
authors.forename: Christian
authors.initials: C
authors.lastname: Malaveille
authors.forename: Alison
authors.initials: A
authors.lastname: Dunning
authors.forename: Kim
authors.initials: K
authors.lastname: Overvad
authors.forename: Anne
authors.initials: A
authors.lastname: Tjønneland
authors.forename: Eiliv
authors.initials: E
authors.lastname: Lund
authors.forename: Françoise
authors.initials: F
authors.lastname: Clavel-Chapelon
authors.forename: Heiner
authors.initials: H
authors.lastname: Boeing
authors.forename: Antonia
authors.initials: A
authors.lastname: Trichopoulou
authors.forename: Domenico
authors.initials: D
authors.lastname: Palli
authors.forename: Vittorio
authors.initials: V
authors.lastname: Krogh
authors.forename: Rosario
authors.initials: R
authors.lastname: Tumino
authors.forename: Salvatore
authors.initials: S
authors.lastname: Panico
authors.forename: H Bas
authors.initials: HB
authors.lastname: Bueno-de-Mesquita
authors.forename: Petra H
authors.initials: PH
authors.lastname: Peeters
authors.forename: Guillem
authors.initials: G
authors.lastname: Pera
authors.forename: Carmen
authors.initials: C
authors.lastname: Martinez
authors.forename: Miren
authors.initials: M
authors.lastname: Dorronsoro
authors.forename: Aurelio
authors.initials: A
authors.lastname: Barricarte
authors.forename: Carmen
authors.initials: C
authors.lastname: Navarro
authors.forename: José Ramón
authors.initials: JR
authors.lastname: Quirós
authors.forename: Göran
authors.initials: G
authors.lastname: Hallmans
authors.forename: Nicholas E
authors.initials: NE
authors.lastname: Day
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Key
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Saracci
authors.forename: Rudolf
authors.initials: R
authors.lastname: Kaaks
authors.forename: Elio
authors.initials: E
authors.lastname: Riboli
authors.forename: Pierre
authors.initials: P
authors.lastname: Hainaut
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D004247:DNA / Q000097:blood / Q000235:genetics*; D005260:Female; D016158:Genes, p53; D006801:Humans; D007938:Leukemia / Q000097:blood / Q000235:genetics*; D008137:Longitudinal Studies; D008175:Lung Neoplasms / Q000097:blood / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011446:Prospective Studies; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D001749:Urinary Bladder Neoplasms / Q000097:blood / Q000235:genetics*; D018631:ras Proteins
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D004247:DNA; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins