Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
Department of Paediatric Oncology, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
Cancer Gene Ther. 2024 Jun;31(6):805-806. doi: 10.1038/s41417-024-00749-9. Epub 2024 Feb 26.
Osteosarcoma is the most prevalent malignant bone tumour in children, adolescents and young adults. Despite a multitude of aberrations present in osteosarcoma genomes, no recurrent driver mutations have been identified to date. In addition, unlike for other sarcoma entities, no functional fusion proteins resulting from chromosomal rearrangements have been reported. Part of the genetic complexity of osteosarcoma might, however, be explained by the association of osteosarcoma with germline and somatic mutations of the major tumour suppressor TP53 that safeguards genomic integrity. By demonstrating that TP53 promoter translocations resulting in transcriptionally active fusion genes are a recurrent event in osteosarcoma, long-learnt paradigms are challenged by a recent publication by Saba, Difilippo et al. Osteosarcoma no longer appears to be a fusion-negative tumour, and by hardwiring cellular stress responses that transactivate the TP53 promoter to an oncogenic fusion partner, TP53 can be subverted and turned into an oncogene.
骨肉瘤是儿童、青少年和青年中最常见的恶性骨肿瘤。尽管骨肉瘤基因组中存在多种异常，但迄今为止尚未确定反复出现的驱动突变。此外，与其他肉瘤实体不同，尚未报道源自染色体重排的功能性融合蛋白。然而，骨肉瘤的部分遗传复杂性可能与骨肉瘤与主要肿瘤抑制因子 TP53 的种系和体细胞突变相关，TP53 可保护基因组完整性。通过证明导致转录活性融合基因的 TP53 启动子易位是骨肉瘤中的一种反复发生的事件，Saba、Difilippo 等人的最近一项出版物对长期以来的范式提出了挑战。骨肉瘤似乎不再是一种融合阴性肿瘤，并且通过将细胞应激反应硬连线到致癌融合伴侣，从而激活 TP53 启动子，TP53 可以被颠覆并转化为癌基因。
