Henderson Stephen, Chakravarthy Ankur, Su Xiaoping, Boshoff Chris, Fenton Tim Robert
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.
Department of Oncology, UCL Cancer Institute, University College London, London WC1E 6BT, UK.
Cell Rep. 2014 Jun 26;7(6):1833-41. doi: 10.1016/j.celrep.2014.05.012. Epub 2014 Jun 5.
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.
载脂蛋白B mRNA编辑酶催化多肽样3B（APOBEC3B）胞嘧啶脱氨酶活性最近已成为人类癌症中一种重要的诱变因素。在病毒感染的细胞中会诱导APOBEC活性，并且在宫颈癌（CESC）中APOBEC特征性突变高频出现，其中超过99%是由人乳头瘤病毒（HPV）引起的。我们通过比较癌症基因组图谱计划测序的HPV阳性和HPV阴性头颈部鳞状细胞癌（HNSCC）的外显子组，来测试APOBEC介导的诱变在HPV相关肿瘤中是否特别重要。正如预期的那样，HPV阴性HNSCC显示出与吸烟相关的突变特征，而我们的数据表明，HPV阳性HNSCC中外源性致癌物暴露的减少产生了一种选择压力，有利于出现具有APOBEC介导的驱动突变的肿瘤。最后，我们提供证据表明，APOBEC活性是多种癌症中PIK3CA基因螺旋结构域热点突变产生的原因。我们的研究结果表明，APOBEC活性是PIK3CA诱变和HPV诱导转化的关键驱动因素。
