PDF(Pubmed)
Abstract：
Objectives: This study combines two innovative mouse models in a major gene discovery project to assess the influence of host genetics on asbestos related disease (ARD). Conventional genetics studies provided evidence that some susceptibility to mesothelioma is genetic. However, the identification of host modifier genes, the roles they may play, and whether they contribute to disease susceptibility remain unknown. Here we report a study designed to rapidly identify genes associated with mesothelioma susceptibility by combining the Collaborative Cross (CC) resource with the well-characterised MexTAg mesothelioma mouse model. Methods: The CC is a powerful mouse resource that harnesses over 90% of common genetic variation in the mouse species, allowing rapid identification of genes mediating complex traits. MexTAg mice rapidly, uniformly, and predictably develop mesothelioma, but only after asbestos exposure. To assess the influence of host genetics on ARD, we crossed 72 genetically distinct CC mouse strains with MexTAg mice and exposed the resulting CC-MexTAg (CCMT) progeny to asbestos and monitored them for traits including overall survival, the time to ARD onset (latency), the time between ARD onset and euthanasia (disease progression) and ascites volume. We identified phenotype-specific modifier genes associated with these traits and we validated the role of human orthologues in asbestos-induced carcinogenesis using human mesothelioma datasets. Results: We generated 72 genetically distinct CCMT strains and exposed their progeny (2,562 in total) to asbestos. Reflecting the genetic diversity of the CC, there was considerable variation in overall survival and disease latency. Surprisingly, however, there was no variation in disease progression, demonstrating that host genetic factors do have a significant influence during disease latency but have a limited role once disease is established. Quantitative trait loci (QTL) affecting ARD survival/latency were identified on chromosomes 6, 12 and X. Of the 97-protein coding candidate modifier genes that spanned these QTL, eight genes (CPED1, ORS1, NDUFA1, HS1BP3, IL13RA1, LSM8, TES and TSPAN12) were found to significantly affect outcome in both CCMT and human mesothelioma datasets. Conclusion: Host genetic factors affect susceptibility to development of asbestos associated disease. However, following mesothelioma establishment, genetic variation in molecular or immunological mechanisms did not affect disease progression. Identification of multiple candidate modifier genes and their human homologues with known associations in other advanced stage or metastatic cancers highlights the complexity of ARD and may provide a pathway to identify novel therapeutic targets.
摘要：
目标：本研究在一项重大基因发现项目中结合了两个创新的小鼠模型，以评估宿主遗传学对石棉相关疾病（ARD）的影响。常规遗传学研究提供的证据表明间皮瘤的某些易感性是遗传的。然而,宿主修饰基因的鉴定，他们可能扮演的角色，它们是否有助于疾病易感性仍然未知。在这里，我们报告了一项旨在通过将协作交叉（CC）资源与特征良好的MexTAG间皮瘤小鼠模型相结合来快速鉴定与间皮瘤易感性相关的基因的研究。方法：CC是一种强大的小鼠资源，利用了小鼠物种90％以上的常见遗传变异，允许快速鉴定介导复杂性状的基因。MexTAG小鼠迅速，统一，可以预测会发展间皮瘤，但只有在接触石棉之后。为了评估宿主遗传学对ARD的影响，我们将72个遗传上不同的CC小鼠品系与MexTAG小鼠杂交，并将所得的CC-MexTAG（CCMT）后代暴露于石棉，并监测它们的性状，包括总体存活率，ARD开始的时间(潜伏期)，ARD发作和安乐死之间的时间（疾病进展）和腹水体积。我们确定了与这些性状相关的表型特异性修饰基因，并使用人类间皮瘤数据集验证了人类直系同源物在石棉诱导的致癌作用。结果：我们产生了72个遗传上不同的CCMT菌株，并将其后代（总共2,562个）暴露于石棉。反映了CC的遗传多样性，总体生存率和疾病潜伏期有相当大的差异.令人惊讶的是,然而,疾病进展没有变化，表明宿主遗传因素在疾病潜伏期确实有显著影响，但一旦疾病确定，其作用有限。在6号、12号和X号染色体上鉴定了影响ARD存活/潜伏期的数量性状基因座（QTL）。在跨越这些QTL的97蛋白编码候选修饰基因中，在CCMT和人类间皮瘤数据集中，发现八个基因（CPED1，ORS1，NDUFA1，HS1BP3，IL13RA1，LSM8，TES和TSPAN12）显着影响结果。结论：宿主遗传因素影响石棉相关疾病的发生。然而,间皮瘤建立后，分子或免疫机制的遗传变异不影响疾病进展.在其他晚期或转移性癌症中与已知关联的多个候选修饰基因及其人类同源物的鉴定突出了ARD的复杂性，并可能提供鉴定新的治疗靶标的途径。
