title: Inactivating CUX1 mutations promote tumorigenesis.
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.
authors: 1] Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK. [2] Department of Haematology, University of Cambridge, Hills Road, Cambridge, UK.
authors: Chi C
authors: CC
authors: Wong
authors: The Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
authors: Inigo
authors: I
authors: Martincorena
authors: Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
authors: Alistair G
authors: AG
authors: Rust
authors: Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
authors: Mamunur
authors: M
authors: Rashid
authors: The Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
authors: Constantine
authors: C
authors: Alifrangis
authors: The Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
authors: Ludmil B
authors: 0000000335964515
authors: LB
authors: Alexandrov
authors: Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
authors: Jessamy C
authors: JC
authors: Tiffen
authors: 1] Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK. [2].
authors: Christina
authors: C
authors: Kober
authors: 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.
authors: Anthony R
authors: AR
authors: Green
authors: 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.
authors: Charles E
authors: CE
authors: Massie
authors: 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.
authors: Jyoti
authors: J
authors: Nangalia
authors: Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
authors: Stella
authors: S
authors: Lempidaki
authors: Department of Internal Medicine III, University of Ulm, Ulm, Germany.
authors: Hartmut
authors: H
authors: Döhner
authors: Department of Internal Medicine III, University of Ulm, Ulm, Germany.
authors: Konstanze
authors: K
authors: Döhner
authors: Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
authors: Sarah J
authors: SJ
authors: Bray
authors: The Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
authors: Ultan
authors: U
authors: McDermott
authors: The Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
authors: Elli
authors: E
authors: Papaemmanuil
authors: 1] Department of Haematology, University of Cambridge, Hills Road, Cambridge, UK. [2] The Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
authors: Peter J
authors: PJ
authors: Campbell
authors: Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
authors: David J
authors: DJ
authors: Adams
mesh_terms: D000818:Animals; D004251:DNA Transposable Elements; D004330:Drosophila / Q000235:genetics; D005260:Female; D016147:Genes, Tumor Suppressor; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016254:Mutagenesis, Insertional; D009154:Mutation; D009369:Neoplasms / Q000235:genetics*; D009374:Neoplasms, Experimental / Q000235:genetics / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors; D023041:Xenograft Model Antitumor Assays
chemical_list: D004251:DNA Transposable Elements; D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009687:Nuclear Proteins; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D012097:Repressor Proteins; D014157:Transcription Factors; C080632:CUX1 protein, human; C521076:PIK3IP1 protein, human; C487757:Pten protein, mouse