Mauduit Olivier, Brulard Céline, Lesluyes Tom, Delcroix Vanessa, Pérot Gaëlle, Choublier Nina, Michaud Mickael, Baud Jessica, Lagarde Pauline, Aurias Alain, Coindre Jean-Michel, Lartigue Lydia, Blay Jean-Yves, Chibon Frédéric
Inserm U1218, Bergonié Cancer Institute, F-33076 Bordeaux, France.
ED 340 BMIC, Claude Bernard Lyon 1 University, F-69622 Villeurbanne, France.
Cancers (Basel). 2019 Jan 11;11(1):81. doi: 10.3390/cancers11010081.
Half of soft-tissue sarcomas are tumors with complex genomics, which display no specific genetic alterations and respond poorly to treatment. It is therefore necessary to find new therapeutic targets for these sarcomas. Despite genetic heterogeneity across samples, oncogenesis may be driven by common pathway alterations. Therefore, genomic and transcriptomic profiles of 106 sarcomas with complex genomics were analyzed to identify common pathways with altered genes. This brought out a gene belonging to the "cell cycle" biological pathway, (RCC1 And BTB Domain Containing Protein 1), which is lost and downregulated in 62.5% of metastatic tumors against 34% of non-metastatic tumors. A retrospective study of three sarcoma cohorts revealed that low expression is prognostic for metastatic progression, specifically in patients that received chemotherapy. In vitro and in vivo, RCBTB1 overexpression in leiomyosarcoma cells specifically sensitized to docetaxel-induced apoptosis. This was associated with increased mitotic rate in vitro and higher growth rate of xenografts. By contrast, inhibition decreased cell proliferation and protected sarcoma cells from apoptosis induced by docetaxel. Collectively, these data evidenced that is frequently deleted in sarcomas with complex genomics and that its downregulation is associated with a higher risk of developing metastasis for patients receiving chemotherapy, likely due to their higher resistance to docetaxel.
软组织肉瘤中有一半是具有复杂基因组学的肿瘤，这些肿瘤没有特定的基因改变，对治疗反应不佳。因此，有必要为这些肉瘤寻找新的治疗靶点。尽管样本间存在基因异质性，但肿瘤发生可能由共同的信号通路改变驱动。因此，对106例具有复杂基因组学的肉瘤的基因组和转录组图谱进行了分析，以确定基因改变的共同信号通路。这揭示了一个属于“细胞周期”生物学通路的基因（含RCC1和BTB结构域蛋白1），该基因在62.5%的转移性肿瘤中缺失并下调，而非转移性肿瘤中这一比例为34%。对三个肉瘤队列的回顾性研究表明，低表达对转移进展具有预后价值，特别是在接受化疗的患者中。在体外和体内，平滑肌肉瘤细胞中RCBTB1的过表达使细胞对多西他赛诱导的凋亡特别敏感。这与体外有丝分裂率增加和异种移植物生长速率提高有关。相比之下，抑制作用降低了细胞增殖，并保护肉瘤细胞免受多西他赛诱导的凋亡。总的来说，这些数据表明，在具有复杂基因组学的肉瘤中，该基因经常缺失，其下调与接受化疗的患者发生转移的风险较高有关，这可能是由于他们对多西他赛的耐药性较高。
