Centre Hospitalier Intercommunal de Créteil, Service de Pneumologie et de Pathologie Professionnelle, Créteil F-94000, France.
Mutagenesis. 2013 May;28(3):323-31. doi: 10.1093/mutage/get008. Epub 2013 Feb 22.
Given the interest in defining biomarkers of asbestos exposure and to provide insights into asbestos-related and cell-specific mechanisms of neoplasia, the identification of gene alterations in asbestos-related cancers can help to a better understanding of exposure risk. To understand the aetiology of asbestos-induced malignancies and to increase our knowledge of mesothelial carcinogenesis, we compared genetic alterations in relevant cancer genes between lung cancer, induced by asbestos and tobacco smoke, and malignant pleural mesothelioma (MPM), a cancer related to asbestos, but not to tobacco smoke. TP53, KRAS, EGFR and NF2 gene alteration analyses were performed in 100 non-small cell lung cancer (NSCLC) patients, 50 asbestos-exposed and 50 unexposed patients, matched for age, gender, histology and smoking habits. Detailed assessment of asbestos exposure was based on both specific questionnaires and asbestos body quantification in lung tissue. Genetic analyses were also performed in 34 MPM patients. TP53, EGFR and KRAS mutations were found in NSCLC with no link with asbestos exposure. NF2 was only altered in MPM. Significant enhancement of TP53 G:C to T:A transversions was found in NSCLC from asbestos-exposed patients when compared with unexposed patients (P = 0.037). Interestingly, TP53 polymorphisms in intron 7 (rs12947788 and rs12951053) were more frequently identified in asbestos-exposed NSCLC (P = 0.046) and MPM patients than in unexposed patients (P < 0.001 and P = 0.012, respectively). These results emphasise distinct genetic alterations between asbestos-related thoracic tumours, but identify common potential susceptibility factors, i.e. single nucleotide polymorphisms in intron 7 of TP53. While genetic changes in NSCLC are dominated by the effects of tobacco smoke, the increase of transversions in TP53 gene is consistent with a synergistic effect of asbestos. These results may help to define cell-dependent mechanisms of action of asbestos and identify susceptibility factors to asbestos.
鉴于人们对确定石棉暴露的生物标志物以及深入了解与石棉相关的和细胞特异性的肿瘤发生机制有着浓厚的兴趣，因此，确定与石棉相关的癌症中的基因改变有助于更好地了解暴露风险。为了了解石棉诱导的恶性肿瘤的病因，并增加我们对间皮细胞癌变的认识，我们比较了与石棉相关但与烟草烟雾无关的癌症（恶性胸膜间皮瘤，MPM）和由石棉和烟草烟雾共同作用引起的肺癌中相关癌症基因的遗传改变。在 100 名非小细胞肺癌（NSCLC）患者、50 名暴露于石棉的患者和 50 名未暴露于石棉的患者中进行了 TP53、KRAS、EGFR 和 NF2 基因改变分析，这些患者在年龄、性别、组织学和吸烟习惯方面相匹配。石棉暴露的详细评估是基于特定问卷和肺组织中石棉体的定量。还对 34 名 MPM 患者进行了基因分析。在 NSCLC 中发现了与石棉暴露无关的 TP53、EGFR 和 KRAS 突变，而 NF2 仅在 MPM 中发生改变。与未暴露于石棉的患者相比，暴露于石棉的 NSCLC 患者中发现 TP53 G:C 到 T:A 颠换的显著增强（P = 0.037）。有趣的是，在暴露于石棉的 NSCLC 和 MPM 患者中，TP53 内含子 7 中的多态性（rs12947788 和 rs12951053）比未暴露于石棉的患者更频繁地被识别（P = 0.046 和 P < 0.001，P = 0.012）。这些结果强调了与石棉相关的胸部肿瘤之间存在明显的遗传改变，但也确定了共同的潜在易感性因素，即 TP53 内含子 7 中的单核苷酸多态性。虽然 NSCLC 的遗传变化主要受烟草烟雾的影响，但 TP53 基因中颠换的增加与石棉的协同作用一致。这些结果可能有助于确定石棉的细胞依赖性作用机制，并确定石棉的易感性因素。
