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Nat Genet. 2014 Jan;46(1):33-8. doi: 10.1038/ng.2846. Epub 2013 Dec 8.

Inactivating CUX1 mutations promote tumorigenesis.

Author information

1
1] Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK. [2] Department of Haematology, University of Cambridge, Hills Road, Cambridge, UK.
2
The Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
3
Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
4
1] Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK. [2].
5
1] Department of Haematology, University of Cambridge, Hills Road, Cambridge, UK. [2] Cambridge Institute for Medical Research, University of Cambridge, Hills Road, Cambridge, UK. [3] Wellcome Trust/MRC Stem Cell Institute, University of Cambridge, Cambridge, UK.
6
Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
7
Department of Internal Medicine III, University of Ulm, Ulm, Germany.
8
1] Department of Haematology, University of Cambridge, Hills Road, Cambridge, UK. [2] The Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.

Abstract

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.

PMID:
24316979
PMCID:
PMC3874239
DOI:
10.1038/ng.2846
[Indexed for MEDLINE]
Free PMC Article

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