文章：

肉瘤基因组学研究进展及新的治疗靶点

Advances in sarcoma genomics and new therapeutic targets

原文发布日期：2011-07-14

DOI: 10.1038/nrc3087

类型: Review Article

开放获取: 否

要点：

1. Human sarcomas are uncommon malignancies that arise from mesenchymal cell types, have varied genetic origins and are clinically heterogeneous. Many sarcomas arise de novo, driven by a single genetic abnormality, and some are progressive and harbour complex genomes.
2. Three core and context-dependent molecular mechanisms drive sarcomagenesis: dysregulation of gene expression by aberrant, chimeric transcription factors generated by specific gene fusions in translocation-associated sarcomas, somatic mutations affecting key signalling pathways and DNA copy-number abnormalities.
3. Novel genomic findings from diverse approaches in sarcoma are identifying point mutations that co-occur with translocations, lineage-specific oncogenes, chromosome remodelling events, and both genomic alterations and mutations that alter canonical signalling and differentiation pathways.
4. As integrative genomics and massively parallel sequencing increase the pace of discovery for the most common lesions in all but the rarest sarcomas, this necessitates renewed focus on developing in vitro and in vivo sarcoma models for accompanying target discovery and functional annotation of sarcoma genomes with genomics-guided functional genetics.
5. Although conventional modalities predominate in sarcoma treatment, new approaches to target aberrant signalling with specific therapies, overcome acquired resistance and target unconventional pathways are rapidly evolving.

要点翻译：

1. 人类肉瘤是一类源于间充质细胞类型的罕见恶性肿瘤，具有多样化的遗传起源和临床异质性。许多肉瘤由单一遗传异常驱动而原发形成，部分则呈进行性发展且携带复杂基因组。
2. 肉瘤发生由三种核心且依赖背景的分子机制驱动：易位相关肉瘤中特定基因融合产生的嵌合转录因子通过异常调控基因表达；影响关键信号通路和DNA拷贝数异常的体细胞突变。
3. 通过多种研究方法获得的新型基因组学发现，正在识别出与易位共存的关键突变、谱系特异性癌基因、染色体重构事件，以及改变经典信号传导和分化通路的基因组改变与突变。
4. 随着整合基因组学和大规模并行测序技术加速了对除最罕见肉瘤外所有常见病变的发现进程，这迫切需要重新聚焦于开发体外和体内肉瘤模型，以配合靶点发现和基因组学引导的功能遗传学对肉瘤基因组进行功能注释。
5. 尽管传统治疗模式在肉瘤治疗中仍占主导地位，但针对异常信号传导的靶向疗法、克服获得性耐药及靶向非常规通路的新策略正在快速发展。

英文摘要：

Increasingly, human mesenchymal malignancies are being classified by the abnormalities that drive their pathogenesis. Although many of these aberrations are highly prevalent within particular sarcoma subtypes, few are currently targeted therapeutically. Indeed, most subtypes of sarcoma are still treated with traditional therapeutic modalities, and in many cases sarcomas are resistant to adjuvant therapies. In this Review, we discuss the core molecular determinants of sarcomagenesis and emphasize the emerging genomic and functional genetic approaches that, coupled with novel therapeutic strategies, have the potential to transform the care of patients with sarcoma.

摘要翻译： 

越来越多的人类间叶源性恶性肿瘤正依据驱动其发病的异常改变进行分类。尽管其中许多畸变在特定肉瘤亚型中高度富集，但目前能靶向干预的极少。事实上，大部分肉瘤亚型仍依赖传统治疗手段，且多数情况下对辅助治疗耐药。本文综述肉瘤发生的核心分子决定因素，重点介绍新兴的基因组与功能遗传学策略，并阐述如何将其与新型治疗手段结合，以改变肉瘤患者的诊疗前景。

原文链接：

Advances in sarcoma genomics and new therapeutic targets