APOBEC-Mediated Cytosine Deamination Links PIK3CA Helical Domain Mutations to Human Papillomavirus-Driven Tumor Development

被引:283
作者
Henderson, Stephen [1 ,2 ]
Chakravarthy, Ankur [1 ]
Su, Xiaoping [3 ]
Boshoff, Chris [1 ]
Fenton, Tim Robert [1 ]
机构
[1] UCL, Inst Canc, Dept Oncol, London WC1E 6BT, England
[2] UCL, Inst Canc, Bill Lyons Informat Ctr, London WC1E 6BT, England
[3] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA
关键词
CYTIDINE DEAMINASE; NECK-CANCER; HEAD; DNA; MUTAGENESIS; EXPRESSION; CARCINOMA; HPV; SIGNATURES; LANDSCAPE;
D O I
10.1016/j.celrep.2014.05.012
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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.
引用
收藏
页码:1833 / 1841
页数:9
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