Human Genetics Foundation, HuGeF, Turin, Italy.
PLoS One. 2013 Apr 23;8(4):e61253. doi: 10.1371/journal.pone.0061253. Print 2013.
Asbestos exposure is the main risk factor for malignant pleural mesothelioma (MPM), a rare aggressive tumor. Nevertheless, only 5-17% of those exposed to asbestos develop MPM, suggesting the involvement of other environmental and genetic risk factors. To identify the genetic risk factors that may contribute to the development of MPM, we conducted a genome-wide association study (GWAS; 370,000 genotyped SNPs, 5 million imputed SNPs) in Italy, among 407 MPM cases and 389 controls with a complete history of asbestos exposure. A replication study was also undertaken and included 428 MPM cases and 1269 controls from Australia. Although no single marker reached the genome-wide significance threshold, several associations were supported by haplotype-, chromosomal region-, gene- and gene-ontology process-based analyses. Most of these SNPs were located in regions reported to harbor aberrant alterations in mesothelioma (SLC7A14, THRB, CEBP350, ADAMTS2, ETV1, PVT1 and MMP14 genes), causing at most a 2-3-fold increase in MPM risk. The Australian replication study showed significant associations in five of these chromosomal regions (3q26.2, 4q32.1, 7p22.2, 14q11.2, 15q14). Multivariate analysis suggested an independent contribution of 10 genetic variants, with an Area Under the ROC Curve (AUC) of 0.76 when only exposure and covariates were included in the model, and of 0.86 when the genetic component was also included, with a substantial increase of asbestos exposure risk estimation (odds ratio, OR: 45.28, 95% confidence interval, CI: 21.52-95.28). These results showed that genetic risk factors may play an additional role in the development of MPM, and that these should be taken into account to better estimate individual MPM risk in individuals who have been exposed to asbestos.
石棉暴露是恶性胸膜间皮瘤（MPM）的主要危险因素，这是一种罕见的侵袭性肿瘤。然而，只有 5-17%接触过石棉的人会发展为 MPM，这表明还存在其他环境和遗传危险因素。为了确定可能导致 MPM 发展的遗传危险因素，我们在意大利进行了一项全基因组关联研究（GWAS；370,000 个基因分型 SNP，500 万个推断 SNP），其中包括 407 例 MPM 病例和 389 例有完整石棉暴露史的对照。还进行了一项复制研究，其中包括来自澳大利亚的 428 例 MPM 病例和 1269 例对照。尽管没有单个标记达到全基因组显著阈值，但基于单体型、染色体区域、基因和基因本体过程的分析支持了几个关联。这些 SNP 大多数位于报道中存在间皮瘤异常改变的区域（SLC7A14、THRB、CEBP350、ADAMTS2、ETV1、PVT1 和 MMP14 基因），导致 MPM 风险增加 2-3 倍。澳大利亚的复制研究表明，在其中五个染色体区域（3q26.2、4q32.1、7p22.2、14q11.2、15q14）存在显著关联。多变量分析表明，10 个遗传变异具有独立贡献，当仅在模型中包含暴露和协变量时，ROC 曲线下面积（AUC）为 0.76，当还包括遗传成分时，AUC 为 0.86，并且大大增加了石棉暴露风险估计（比值比，OR：45.28，95%置信区间，CI：21.52-95.28）。这些结果表明，遗传危险因素可能在 MPM 的发展中起额外作用，并且在考虑到已暴露于石棉的个体的个体 MPM 风险时，应考虑这些因素。
