Molecular Carcinogenesis Group, International Agency for Research on Cancer, Lyon, France.
Environ Health Perspect. 2011 Nov;119(11):1635-40. doi: 10.1289/ehp.1103539. Epub 2011 Jul 18.
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.
We evaluated seasonal variation in R249S and HBV in relation to AFB1 exposure.
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).
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.
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.
在气候炎热潮湿的国家，慢性乙型肝炎病毒（HBV）感染和饮食黄曲霉毒素 B1（AFB1）暴露是肝细胞癌（HCC）的病因。HCC 常携带肿瘤蛋白 p53（TP53）密码子 249 处的突变（R249S）。在慢性携带者中，HBV X 基因中的 1762T/1764A 突变与 HCC 风险增加相关。这两种突变都已在无症状 HBV 携带者的循环无细胞 DNA（cfDNA）中检测到。
我们评估了 R249S 和 HBV 与 AFB1 暴露相关的季节性变化。
在冈比亚三个村庄进行的一项为期 10 个月的横断面研究中，通过质谱法在 473 名无症状受试者（237 名 HBV 携带者和 236 名非携带者）的 cfDNA 中定量检测 R249S。通过定量聚合酶链反应检测 1762T/1764A HBV 突变。此外，对 99 名 HBsAg 阳性的受试者进行了 HBV S 基因测序。
我们观察到血清 R249S 水平的季节性变化。在 4 月至 7 月间接受调查的 HBsAg 阳性受试者中，R249S 阳性和平均浓度显著较高（61%；5690±11300 R249S 拷贝/ml 血清），而在 10 月至 3 月接受调查的受试者中则较低（32%和 480±1030 拷贝/ml 血清（比值比=3.59；95%置信区间：2.05，6.30；p<0.001））。HBV e 抗原（HBeAg）（HBV 复制的标志物）的阳性率和病毒 DNA 载量也呈季节性变化，4 月至 6 月接受调查的 15%至 30%的受试者 HBeAg 阳性，而其他月份接受调查的受试者中<10%。我们在 8%的携带者中检测到 1762T/1764A 突变，其中一半的携带者 R249S 阳性。在 99 名 HBsAg 阳性的受试者中，我们发现了 95 名 HBV 基因型 E。
无症状受试者的 cfDNA 中可检测到 R249S。时间和定量变化的证据表明，AFB1 暴露、HBV 阳性和复制之间存在相互作用，可能影响 TP53 突变的形成或持续存在。
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