1] Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK. [2] Department of Haematology, University of Cambridge, Hills Road, Cambridge, UK.
The Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
Nat Genet. 2014 Jan;46(1):33-8. doi: 10.1038/ng.2846. Epub 2013 Dec 8.
A major challenge in cancer genetics is to determine which low-frequency somatic mutations are drivers of tumorigenesis. Here we interrogate the genomes of 7,651 diverse human cancers and find inactivating mutations in the homeodomain transcription factor gene CUX1 (cut-like homeobox 1) in ~1-5% of various tumors. Meta-analysis of CUX1 mutational status in 2,519 cases of myeloid malignancies reveals disruptive mutations associated with poor survival, highlighting the clinical significance of CUX1 loss. In parallel, we validate CUX1 as a bona fide tumor suppressor using mouse transposon-mediated insertional mutagenesis and Drosophila cancer models. We demonstrate that CUX1 deficiency activates phosphoinositide 3-kinase (PI3K) signaling through direct transcriptional downregulation of the PI3K inhibitor PIK3IP1 (phosphoinositide-3-kinase interacting protein 1), leading to increased tumor growth and susceptibility to PI3K-AKT inhibition. Thus, our complementary approaches identify CUX1 as a pan-driver of tumorigenesis and uncover a potential strategy for treating CUX1-mutant tumors.
癌症遗传学的一个主要挑战是确定哪些低频体细胞突变是肿瘤发生的驱动因素。在这里，我们分析了 7651 种不同人类癌症的基因组，发现了大约 1-5%的各种肿瘤中同源域转录因子基因 CUX1（cut-like homeobox 1）的失活突变。在 2519 例髓系恶性肿瘤的 CUX1 突变状态的荟萃分析中，揭示了与不良预后相关的破坏性突变，突出了 CUX1 缺失的临床意义。同时，我们使用小鼠转座子介导的插入诱变和果蝇癌症模型验证了 CUX1 是一种真正的肿瘤抑制因子。我们证明 CUX1 缺乏通过直接转录下调 PI3K 抑制剂 PIK3IP1（磷酸肌醇 3-激酶相互作用蛋白 1）激活磷酸肌醇 3-激酶（PI3K）信号通路，导致肿瘤生长增加和对 PI3K-AKT 抑制的敏感性增加。因此，我们的互补方法确定 CUX1 为肿瘤发生的泛驱动因子，并揭示了治疗 CUX1 突变肿瘤的潜在策略。
