School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China.
Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
Hepatology. 2021 Jul;74(1):264-280. doi: 10.1002/hep.31723. Epub 2021 Jun 15.
Mutational signature analyses are an effective tool in identifying cancer etiology. Humans are frequently exposed to pyrrolizidine alkaloids (PAs), the most common carcinogenic phytotoxins widely distributed in herbal remedies and foods. However, due to the lack of human epidemiological data, PAs are classified as group II hepatocarcinogens by the World Health Organization. This study identified a PA mutational signature as the biomarker to investigate the association of PA exposure with human liver cancer.
Pyrrole-protein adducts (PPAs), the PA exposure biomarker, were measured and found in 32% of surgically resected specimens from 34 patients with liver cancer in Hong Kong. Next, we delineated the mode of mutagenic and tumorigenic actions of retrorsine, a representative PA, in mice and human hepatocytes (HepaRG). Retrorsine induced DNA adduction, DNA damage, and activation of tumorigenic hepatic progenitor cells, which initiated hepatocarcinogenesis. PA mutational signature, as the unique molecular fingerprint of PA-induced mutation, was derived from exome mutations in retrorsine-exposed mice and HepaRG cells. Notably, PA mutational signature was validated in genomes of patients with PPA-positive liver cancer but not patients with PPA-negative liver cancer, confirming the specificity of this biomarker in revealing PA-associated liver cancers. Furthermore, we examined the established PA mutational signature in 1,513 liver cancer genomes and found that PA-associated liver cancers were potentially prevalent in Asia (Mainland China [48%], Hong Kong [44%], Japan [22%], South Korea [6%], Southeast Asia [25%]) but minor in Western countries (North America [3%] and Europe [5%]).
This study provides a clinical indication of PA-associated liver cancer. We discovered an unexpectedly extensive implication of PA exposure in patients with liver cancer, laying the scientific basis for precautionary approaches and prevention of PA-associated human liver cancers.
突变特征分析是确定癌症病因的有效工具。人类经常接触到吡咯里西啶生物碱（PA），这是最常见的致癌植物毒素，广泛存在于草药和食物中。然而，由于缺乏人类流行病学数据，世界卫生组织将 PA 归类为 2B 类肝癌致癌物。本研究鉴定了 PA 突变特征作为生物标志物，以研究 PA 暴露与人类肝癌之间的关联。
在香港 34 名肝癌患者手术切除标本中，有 32%检测到吡咯蛋白加合物（PPA），这是 PA 暴露的生物标志物。接下来，我们在小鼠和人肝细胞（HepaRG）中描绘了 retrorsine （一种代表性的 PA）的诱变和致癌作用模式。Retrorsine 诱导 DNA 加合物、DNA 损伤和肿瘤发生的肝前体细胞激活，从而引发肝癌发生。PA 突变特征是 retrorsine 暴露的小鼠和 HepaRG 细胞中外显子突变的独特分子指纹，源自 PA 诱导的突变。值得注意的是，PA 突变特征在 PPA 阳性肝癌患者的基因组中得到验证，但在 PPA 阴性肝癌患者的基因组中未得到验证，证实了该生物标志物在揭示 PA 相关肝癌中的特异性。此外，我们在 1513 例肝癌基因组中检测到已建立的 PA 突变特征，发现 PA 相关肝癌在亚洲（中国大陆[48%]、香港[44%]、日本[22%]、韩国[6%]、东南亚[25%]）中可能较为普遍，但在西方国家（北美[3%]和欧洲[5%]）中较少见。
本研究为 PA 相关肝癌提供了临床依据。我们发现 PA 暴露在肝癌患者中存在出乎意料的广泛影响，为预防 PA 相关的人类肝癌提供了科学依据。
