title: Seasonal variation in TP53 R249S-mutated serum DNA with aflatoxin exposure and hepatitis B virus infection.
abstract: BACKGROUND
  Chronic hepatitis B virus (HBV) infection and dietary aflatoxin B1 (AFB1) exposure are etiological factors for hepatocellular carcinoma (HCC) in countries with hot, humid climates. HCC often harbors a TP53 (tumor protein p53) mutation at codon 249 (R249S). In chronic carriers, 1762T/1764A mutations in the HBV X gene are associated with increased HCC risk. Both mutations have been detected in circulating cell-free DNA (CFDNA) from asymptomatic HBV carriers.
  
  
  OBJECTIVE
  We evaluated seasonal variation in R249S and HBV in relation to AFB1 exposure.
  
  
  METHODS
  R249S was quantitated by mass spectrometry in CFDNA in a cross-sectional survey of 473 asymptomatic subjects (237 HBV carriers and 236 noncarriers) recruited in three villages in the Gambia over a 10-month period. 1762T/1764A HBV mutations were detected by quantitative polymerase chain reaction. In addition, the HBV S gene was sequenced in 99 subjects positive for HBV surface antigen (HBsAg).
  
  
  RESULTS
  We observed a seasonal variation of serum R249S levels. Positivity for R249S and average concentration were significantly higher in HBsAg-positive subjects surveyed during April-July (61%; 5,690 ± 11,300 R249S copies/mL serum) than in those surveyed October-March [32% and 480 ± 1,030 copies/mL serum (odds ratio = 3.59; 95% confidence interval: 2.05, 6.30; p < 0.001)]. Positivity for HBV e antigen (HBeAg) (a marker of HBV replication) and viral DNA load also varied seasonally, with 15-30% of subjects surveyed between April and June HBeAg positive, compared with < 10% surveyed during other months. We detected 1762T/1764A mutations in 8% of carriers, half of whom were positive for R249S. We found HBV genotype E in 95 of 99 HBsAg-positive subjects.
  
  
  CONCLUSIONS
  R249S is detectable in CFDNA of asymptomatic subjects. Evidence of temporal and quantitative variations suggests an interaction among AFB1 exposure, HBV positivity, and replication on TP53 mutation formation or persistence.
authors.affiliation: Molecular Carcinogenesis Group, International Agency for Research on Cancer, Lyon, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Villar
authors.forename: Emilie
authors.initials: E
authors.lastname: Le Roux-Goglin
authors.forename: Doriane A
authors.initials: DA
authors.lastname: Gouas
authors.forename: Amelie
authors.initials: A
authors.lastname: Plymoth
authors.forename: Gilles
authors.initials: G
authors.lastname: Ferro
authors.forename: Mathieu
authors.initials: M
authors.lastname: Boniol
authors.forename: Myriam
authors.initials: M
authors.lastname: Lereau
authors.forename: Ebrima
authors.initials: E
authors.lastname: Bah
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Hall
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Wild
authors.forename: Maimuna
authors.initials: M
authors.lastname: Mendy
authors.forename: Helene
authors.initials: H
authors.lastname: Norder
authors.forename: Marianne
authors.initials: M
authors.lastname: van der Sande
authors.forename: Hilton
authors.initials: H
authors.lastname: Whittle
authors.forename: Marlin D
authors.initials: MD
authors.lastname: Friesen
authors.forename: John D
authors.initials: JD
authors.lastname: Groopman
authors.forename: Pierre
authors.initials: P
authors.lastname: Hainaut
mesh_terms: D000328:Adult; D000348:Aflatoxins / Q000633:toxicity*; D000368:Aged; D016022:Case-Control Studies; D003430:Cross-Sectional Studies; D004279:DNA, Viral / Q000032:analysis; D005260:Female; D005714:Gambia / Q000453:epidemiology; D006515:Hepatitis B virus; D019694:Hepatitis B, Chronic / Q000453:epidemiology*; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D012307:Risk Factors; D012621:Seasons; D021241:Spectrometry, Mass, Electrospray Ionization; D016159:Tumor Suppressor Protein p53 / Q000097:blood / Q000235:genetics*
chemical_list: D000348:Aflatoxins; D004279:DNA, Viral; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53