Pleural mesothelioma and lung cancer: the role of asbestos exposure and genetic variants in selected iron metabolism and inflammation genes

Two of the major cancerous diseases associated with asbestos exposure are malignant pleural mesothelioma (MPM) and lung cancer (LC). In addition to asbestos exposure, genetic factors have been suggested to be associated with asbestos-related carcinogenesis and lung genotoxicity. While genetic factors involved in the susceptibility to MPM were reported, to date the influence of individual genetic variations on asbestos-related lung cancer risk is still poorly understood. Since inflammation and disruption of iron (Fe) homeostasis are hallmarks of asbestos exposure affecting the pulmonary tissue, this study aimed at investigating the association between Fe-metabolism and inflammasome gene variants and susceptibility to develop LC or MPM, by comparing an asbestos-exposed population affected by LC with an “asbestos-resistant exposed population”. A retrospective approach similar to our previous autopsy-based pilot study was employed in a novel cohort of autoptic samples, thus giving us the possibility to corroborate previous findings obtained on MPM by repeating the analysis in a novel cohort of autoptic samples. The protective role of HEPH coding SNP was further confirmed. In addition, the two non-coding SNPs, either in FTH1 or in TF, emerged to exert a similar protective role in a new cohort of LC exposed individuals from the same geographic area of MPM subjects. No association was found between NLRP1 and NLRP3 polymorphisms with susceptibility to develop MPM and LC. Further research into a specific MPM and LC “genetic signature” may be needed to broaden our knowledge of the genetic landscape attributed to result in MPM and LC.

与石棉暴露相关的主要恶性肿瘤包括恶性胸膜间皮瘤（malignant pleural mesothelioma, MPM）与肺癌（lung cancer, LC）。除石棉暴露外，遗传因素也被认为与石棉相关致癌作用及肺部遗传毒性存在关联。尽管已有研究报道了与恶性胸膜间皮瘤易感性相关的遗传因素，但截至目前，个体遗传变异对石棉相关肺癌发病风险的影响仍鲜为人知。由于炎症反应与铁（Fe）稳态紊乱是石棉暴露损伤肺组织的标志性特征，本研究旨在通过对比罹患肺癌的石棉暴露人群与“石棉暴露耐受人群”，探究铁代谢及炎症小体基因变异与肺癌或恶性胸膜间皮瘤易感性之间的关联。本研究在全新的尸体解剖样本队列中采用了与此前基于尸检的预试验相似的回顾性研究方法，从而得以通过在全新的尸体解剖样本队列中重复分析，验证此前针对恶性胸膜间皮瘤得到的研究结果。HEPH编码区单核苷酸多态性（single nucleotide polymorphism, SNP）的保护作用得到进一步证实。此外，位于FTH1基因或TF基因区域的两个非编码单核苷酸多态性，在来自与恶性胸膜间皮瘤研究对象同一地理区域的肺癌暴露人群新队列中，同样展现出相似的保护作用。未发现NLRP1与NLRP3基因多态性与恶性胸膜间皮瘤及肺癌的易感性存在关联。未来或需针对恶性胸膜间皮瘤与肺癌的特异性“遗传特征”开展进一步研究，以拓展我们对导致两类肿瘤发生的遗传机制的认知。