title: APOBEC-mediated cytosine deamination links PIK3CA helical domain mutations to human papillomavirus-driven tumor development.
abstract: APOBEC3B cytosine deaminase activity has recently emerged as a significant mutagenic factor in human cancer. APOBEC activity is induced in virally infected cells, and APOBEC signature mutations occur at high frequency in cervical cancers (CESC), over 99% of which are caused by human papillomavirus (HPV). We tested whether APOBEC-mediated mutagenesis is particularly important in HPV-associated tumors by comparing the exomes of HPV+ and HPV- head and neck squamous cell carcinomas (HNSCCs) sequenced by The Cancer Genome Atlas project. As expected, HPV- HNSCC displays a smoking-associated mutational signature, whereas our data suggest that reduced exposure to exogenous carcinogens in HPV+ HNSCC creates a selective pressure that favors emergence of tumors with APOBEC-mediated driver mutations. Finally, we provide evidence that APOBEC activity is responsible for the generation of helical domain hot spot mutations in the PIK3CA gene across multiple cancers. Our findings implicate APOBEC activity as a key driver of PIK3CA mutagenesis and HPV-induced transformation.
authors.affiliation: Department of Oncology, UCL Cancer Institute, University College London, London WC1E 6BT, UK; Bill Lyons Informatics Centre, UCL Cancer Institute, University College London, London WC1E 6BT, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Henderson
authors.affiliation: Department of Oncology, UCL Cancer Institute, University College London, London WC1E 6BT, UK.
authors.forename: Ankur
authors.initials: A
authors.lastname: Chakravarthy
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Su
authors.affiliation: Department of Oncology, UCL Cancer Institute, University College London, London WC1E 6BT, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Boshoff
authors.affiliation: Department of Oncology, UCL Cancer Institute, University College London, London WC1E 6BT, UK. Electronic address: t.fenton@ucl.ac.uk.
authors.forename: Tim Robert
authors.initials: TR
authors.lastname: Fenton
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000235:genetics / Q000821:virology*; D002472:Cell Transformation, Viral / Q000235:genetics*; D058534:Class I Phosphatidylinositol 3-Kinases; D003564:Cytidine Deaminase / Q000378:metabolism*; D003596:Cytosine / Q000378:metabolism*; D003641:Deamination; D006258:Head and Neck Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000821:virology*; D006801:Humans; D015778:Minor Histocompatibility Antigens; D009154:Mutation; D027383:Papillomaviridae / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D000077195:Squamous Cell Carcinoma of Head and Neck
chemical_list: D015778:Minor Histocompatibility Antigens; D003596:Cytosine; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C495794:APOBEC3B protein, human; D003564:Cytidine Deaminase