Saba Karim H, Difilippo Valeria, Kovac Michal, Cornmark Louise, Magnusson Linda, Nilsson Jenny, van den Bos Hilda, Spierings Diana Cj, Bidgoli Mahtab, Jonson Tord, Sumathi Vaiyapuri P, Brosjö Otte, Staaf Johan, Foijer Floris, Styring Emelie, Nathrath Michaela, Baumhoer Daniel, Nord Karolin H
Department of Laboratory Medicine, Division of Clinical Genetics, Lund University, Lund, Sweden.
Bone Tumour Reference Centre at the Institute of Pathology, University Hospital and University of Basel, Basel, Switzerland.
J Pathol. 2024 Feb;262(2):147-160. doi: 10.1002/path.6219. Epub 2023 Nov 27.
TP53 is the most frequently mutated gene in human cancer. This gene shows not only loss-of-function mutations but also recurrent missense mutations with gain-of-function activity. We have studied the primary bone malignancy osteosarcoma, which harbours one of the most rearranged genomes of all cancers. This is odd since it primarily affects children and adolescents who have not lived the long life thought necessary to accumulate massive numbers of mutations. In osteosarcoma, TP53 is often disrupted by structural variants. Here, we show through combined whole-genome and transcriptome analyses of 148 osteosarcomas that TP53 structural variants commonly result in loss of coding parts of the gene while simultaneously preserving and relocating the promoter region. The transferred TP53 promoter region is fused to genes previously implicated in cancer development. Paradoxically, these erroneously upregulated genes are significantly associated with the TP53 signalling pathway itself. This suggests that while the classical tumour suppressor activities of TP53 are lost, certain parts of the TP53 signalling pathway that are necessary for cancer cell survival and proliferation are retained. In line with this, our data suggest that transposition of the TP53 promoter is an early event that allows for a new normal state of genome-wide rearrangements in osteosarcoma. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
TP53是人类癌症中最常发生突变的基因。该基因不仅存在功能丧失性突变，还存在具有功能获得性活性的复发性错义突变。我们研究了原发性骨恶性肿瘤骨肉瘤，其拥有所有癌症中重排程度最高的基因组之一。这很奇怪，因为它主要影响儿童和青少年，而他们并没有经历过积累大量突变所需的漫长生命历程。在骨肉瘤中，TP53常常因结构变异而受到破坏。在此，我们通过对148例骨肉瘤进行全基因组和转录组联合分析表明，TP53结构变异通常会导致该基因编码部分的缺失，同时保留并重新定位启动子区域。转移的TP53启动子区域与先前涉及癌症发展的基因融合。矛盾的是，这些错误上调的基因与TP53信号通路本身显著相关。这表明，虽然TP53的经典肿瘤抑制活性丧失，但癌细胞存活和增殖所需的TP53信号通路的某些部分得以保留。与此相符的是，我们的数据表明TP53启动子转位是一个早期事件，它使得骨肉瘤中基因组重排呈现一种新的正常状态。© 2023作者。《病理学杂志》由约翰·威利父子有限公司代表大不列颠及爱尔兰病理学会出版。
