Sarcomas comprise a heterogeneous group of malignant tumors of mesenchymal origin. More than 80 entities are associated with different mesenchymal lineages. Sarcomas with fibroblastic, muscle, bone, vascular, adipocytic, and other characteristics are distinguished. Nearly half of all entities contain specific chromosomal translocations that give rise to fusion proteins. These are mostly pathognomonic, and their detection by various molecular techniques supports histopathologic classification. Moreover, the fusion proteins act as oncogenic drivers, and their blockade represents a promising therapeutic approach. This review summarizes the current knowledge on fusion proteins in sarcoma. We categorize the different fusion proteins into functional classes, including kinases, epigenetic regulators, and transcription factors, and describe their mechanisms of action. Interestingly, while fusion proteins acting as transcription factors are found in all mesenchymal lineages, the others have a more restricted pattern. Most kinase-driven sarcomas belong to the fibroblastic/myofibroblastic lineage. Fusion proteins with an epigenetic function are mainly associated with sarcomas of unclear differentiation, suggesting that epigenetic dysregulation leads to a major change in cell identity. Comparison of mechanisms of action reveals recurrent functional modes, including antagonism of Polycomb activity by fusion proteins with epigenetic activity and recruitment of histone acetyltransferases by fusion transcription factors of the myogenic lineage. Finally, based on their biology, we describe potential approaches to block the activity of fusion proteins for therapeutic intervention. Overall, our work highlights differences as well as similarities in the biology of fusion proteins from different sarcomas and provides the basis for a functional classification.
肉瘤是一组起源于间叶组织的异质性恶性肿瘤，包含80多种与不同间叶谱系相关的亚型。根据成纤维细胞性、肌源性、骨源性、血管性、脂肪细胞性等特征可对其进行区分。近半数肉瘤亚型存在特异性染色体易位，从而产生融合蛋白。这些融合蛋白大多具有疾病特异性，通过多种分子技术检测其表达可为组织病理学分类提供依据。此外，融合蛋白作为致癌驱动因子，其功能阻断已成为极具前景的治疗策略。本综述系统总结了当前肉瘤融合蛋白的研究进展，将不同融合蛋白按功能分为激酶类、表观遗传调控因子类和转录因子类，并阐述其作用机制。值得注意的是，虽然转录因子类融合蛋白存在于所有间叶谱系中，其他类别则呈现更局限的分布模式。大多数激酶驱动型肉瘤属于成纤维细胞/肌成纤维细胞谱系，而具有表观遗传调控功能的融合蛋白主要见于分化不明确的肉瘤亚型，提示表观遗传失调可能导致细胞身份的根本性改变。作用机制的比较研究揭示了重复出现的功能模式，包括表观遗传活性融合蛋白对多梳蛋白活性的拮抗作用，以及肌源性谱系转录因子融合蛋白对组蛋白乙酰转移酶的招募作用。最后，基于融合蛋白的生物学特性，我们探讨了通过阻断其活性实现治疗干预的潜在策略。本研究系统揭示了不同肉瘤融合蛋白生物学特性的共性与差异，为建立功能分类体系奠定了基础。
肿瘤(癌症)患者之家