TP53 and KRAS2 mutations in plasma DNA of healthy subjects and subsequent cancer occurrence: a prospective study.
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.
Gormally
Emmanuelle
E
IARC, 150 Cours Albert Thomas, 69372 Lyon Cedex 08, France.
Vineis
Paolo
P
Matullo
Giuseppe
G
Veglia
Fabrizio
F
Caboux
Elodie
E
Le Roux
Emilie
E
Peluso
Marco
M
Garte
Seymour
S
Guarrera
Simonetta
S
Munnia
Armelle
A
Airoldi
Luisa
L
Autrup
Herman
H
Malaveille
Christian
C
Dunning
Alison
A
Overvad
Kim
K
Tjønneland
Anne
A
Lund
Eiliv
E
Clavel-Chapelon
Françoise
F
Boeing
Heiner
H
Trichopoulou
Antonia
A
Palli
Domenico
D
Krogh
Vittorio
V
Tumino
Rosario
R
Panico
Salvatore
S
Bueno-de-Mesquita
H Bas
HB
Peeters
Petra H
PH
Pera
Guillem
G
Martinez
Carmen
C
Dorronsoro
Miren
M
Barricarte
Aurelio
A
Navarro
Carmen
C
Quirós
José Ramón
JR
Hallmans
Göran
G
Day
Nicholas E
NE
Key
Timothy J
TJ
Saracci
Rodolfo
R
Kaaks
Rudolf
R
Riboli
Elio
E
Hainaut
Pierre
P
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
C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D004247:DNA; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins