Molecular genetics of osteosarcoma.
Molecular genetics of osteosarcoma.
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DOI：
10.1016/j.bone.2016.10.017
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发表时间：
2017-09
期刊：
影响因子：
4.1
通讯作者：
Tao J
中科院分区：
文献类型：
--
作者：
Rickel K;Fang F;Tao J
骨肉瘤是骨癌的主要形式，主要影响青少年。骨肉瘤分子遗传学研究的最新进展改变了我们对骨肉瘤病因和治疗方法的看法。随着我们越来越接近获得常见癌症中候选癌症驱动基因的更完整目录，骨肉瘤中体细胞突变的景观正在从其第一阶段出现。在这篇综述中，我们总结了最近的全基因组和/或全外显子组基因组研究，然后把这些研究结果的背景下，在人类骨肉瘤的体细胞突变和突变过程的遗传标志。其中一个教训是，骨肉瘤基因组的体细胞突变程度和复杂性与常见的成人癌症相似。因此，需要比目前获得的更多数量的样本来完成人类骨肉瘤驱动突变的目录。与此同时，在其他物种的遗传学研究揭示了候选驱动基因及其在骨肉瘤发生中的作用。这篇综述还总结了基因工程小鼠模型（GEMM）中新发现的驱动程序，并讨论了我们对驱动程序的性质和数量对骨肉瘤肿瘤潜伏期，亚型和转移潜力的影响的理解。越来越明显的是，可能需要由三个驱动因素（一个“第一驱动因素”和两个“协同驱动因素”）组成的协同团队来产生一种动物模型，该模型以短的潜伏期重现侵袭性骨肉瘤。最后，迫切需要新的癌症治疗方法来提高骨肉瘤患者的生存率和生活质量。本文综述了骨肉瘤的几个弱点，以探讨下一代分子靶向治疗的可能性。然而，为了完成我们对骨肉瘤体细胞突变基础的理解，开发可靠的人类疾病动物模型，并应用这些信息指导新的治疗方法以降低这种罕见疾病的发病率和死亡率，还有很多工作要做。
Osteosarcoma is the predominant form of bone cancer, affecting mostly adolescents. Recent progress made in molecular genetic studies of osteosarcoma has changed our view on the cause of the disease and ongoing therapeutic approaches for patients. As we draw closer to gaining more complete catalogues of candidate cancer driver genes in common forms of cancer, the landscape of somatic mutations in osteosarcoma is emerging from its first phase. In this review, we summarize recent whole genome and/or whole exome genomic studies, and then put these findings in the context of genetic hallmarks of somatic mutations and mutational processes in human osteosarcoma. One of the lessons learned here is that the extent of somatic mutations and complexity of the osteosarcoma genome are similar to that of common forms of adult cancer. Thus, a much higher number of samples than those currently obtained are needed to complete the catalogue of driver mutations in human osteosarcoma. In parallel, genetic studies in other species have revealed candidate driver genes and their roles in the genesis of osteosarcoma. This review also summarizes newly identified drivers in genetically engineered mouse models (GEMMs) and discusses our understanding of the impact of nature and number of drivers on tumor latency, subtypes, and metastatic potentials of osteosarcoma. It is becoming apparent that a synergistic team composed of three drivers (one ‘first driver’ and two ‘synergistic drivers’) may be required to generate an animal model that recapitulates aggressive osteosarcoma with a short latency. Finally, new cancer therapies are urgently needed to improve survival rate and quality of life for osteosarcoma patients. Several vulnerabilities in osteosarcoma are illustrated in this review to exemplify the opportunities for next generation molecularly targeted therapies. However, much work remains in order to complete our understanding of the somatic mutation basis of osteosarcoma, to develop reliable animal models of human disease, and to apply this information to guide new therapeutic approaches for reducing morbidity and mortality of this rare disease.