Watanabe Masahiko, Haeno Hiroshi, Mimaki Sachiyo, Tsuchihara Katsuya
School of Pharmacy, Shujitsu University, 1-6-1 Nishigawara, Okayama, 703-8516, Japan.
Research Institute for Biomedical Sciences, Tokyo University of Science, 2669 Yamazaki, Noda, Chiba, 277-0022, Japan.
Genes Environ. 2024 Oct 24;46(1):21. doi: 10.1186/s41021-024-00315-7.
Both mutation induction and clonal expansion of mutated cells cause cancer. The probability of cancer development depends on mutations, clonal growth rates, and carcinogenic mechanisms. A recent study showed cases of occupational cholangiocarcinomas that originate multifocally, with higher mutation burden levels than those in common cholangiocarcinomas. This study aimed to identify the effect of clonal expansion on and estimate the risk of occupational and common intrahepatic cholangiocarcinomas (ICCs) using a multistage model modified to include the effect of cell expansion at any carcinogenic stage.
The age-specific incidence of common ICC estimated from the Vital Statistics in Japan and the prognosis of ICC, and mutation frequencies of occupational and common ICC available from the previous report, were applied to a multistage model modified with cell proliferation effects. From the fittest model, the risk after exposure was estimated.
The required number of stages for carcinogenesis was estimated to be three based on the incidences and mutation frequencies of occupational and common ICCs. Based on this estimation, the predicted incidence curve under the model was similar to that estimated from the ICC mortality rate, except for older adults. The model indicated a minor effect of clonal expansion on the observed occupational ICC risk. It predicted a rapid decrease in ICC risk after the cessation of occupational exposure, although the time of clinical detection of cancer after the exposure was affected by latency. The model predicted an increase in cancer risk in older adults caused by cell expansion and common background mutations. However, the risk in older adults was overestimated in the case of common ICC; this divergence could influence occupational ICC cases.
Three-stage ICC carcinogenesis has been proposed. The high mutation burden levels caused by occupational exposure led to an immediate incidence of cancer. After a long period of relatively low cancer risk, an increased risk in older adults was also predicted.
突变诱导和突变细胞的克隆扩增均会引发癌症。癌症发生的概率取决于突变、克隆生长速率和致癌机制。最近一项研究显示，职业性胆管癌病例多灶起源，其突变负担水平高于普通胆管癌。本研究旨在使用一个经过修改的多阶段模型来确定克隆扩增对职业性和普通肝内胆管癌（ICC）的影响，并估计其风险，该模型纳入了任何致癌阶段细胞扩增的影响。
将根据日本生命统计数据估算的普通ICC的年龄别发病率、ICC的预后情况，以及先前报告中可得的职业性和普通ICC的突变频率，应用于一个经过细胞增殖效应修改的多阶段模型。从最适合的模型中，估计暴露后的风险。
根据职业性和普通ICC的发病率及突变频率，估计致癌所需的阶段数为三个。基于这一估计，该模型下预测的发病率曲线与根据ICC死亡率估计的曲线相似，但老年人除外。该模型表明克隆扩增对观察到的职业性ICC风险影响较小。它预测职业暴露停止后ICC风险会迅速下降，尽管暴露后癌症的临床检测时间受潜伏期影响。该模型预测老年人因细胞扩增和常见背景突变导致癌症风险增加。然而，在普通ICC的情况下，老年人的风险被高估了；这种差异可能会影响职业性ICC病例。
已提出ICC致癌为三阶段过程。职业暴露导致的高突变负担水平导致癌症立即发病。在经历了较长时期相对较低的癌症风险后，预计老年人的风险也会增加。
