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.

APOBEC3 genes: retroviral restriction factors to cancer drivers

“…In HNSC and breast cancers a linear relationship between A3 signature mutations and other point mutations across cancers with widely varying mutational loads is observed [35,43], consistent with a model in which various mutagenic processes are kept in check by DNA repair mechanisms and only manifest when these pathways fail. In B cells, for instance, the mutagenic activity of AID is restricted outside of SHM by a combination of BER and MMR [72].…”

“…Consistent with this, HPV16 infection has recently been shown to upregulate A3A and A3B mRNA expression in a keratinocyte cell line, and both are upregulated in pre-invasive cervical lesions [19,45]. However, within cervical cancer and HNSC the enrichment of A3 signature mutations is not related to the expression of A3 genes, at least as seen in the tumor biopsy [43,44]. Of course, it could be that when the mutations are occurring during development of these tumors, they are correlated with the expression of the A3 responsible, but that this relationship is lost following subsequent downregulation; a possibility alluded to by Roberts and Gordenin in their discussion of A3s as transient hypermutators [46].…”

“…The preponderance of A3 mutations in HPV driven cervical cancer, together with the observation that A3 mutations are enriched in the HPVassociated subset of head and neck squamous cell carcinoma (HNSC), suggest a possible off-target response to the virus [37,38,43,44]. Consistent with this, HPV16 infection has recently been shown to upregulate A3A and A3B mRNA expression in a keratinocyte cell line, and both are upregulated in pre-invasive cervical lesions [19,45].…”

“…Further, in hepatocytes expression of several A3s increases following hepatitis B virus (HBV) infection [47]. However there is no sign of off-target A3 mutations following this response, nor are they evident in HBV-associated hepatocellular carcinomas [43,48].…”

“…In exome data, enrichment of A3 mutations amongst putative cancer driver genes as defined by either the catalogue of somatic mutations in cancer (COSMIC) database [73] and/or the MutSig collection [74] of recurrently mutated genes [38,43] have been observed. Upon inspection of the genes most frequently A3-mutated in HPV-associated cancers, the PIK3CA proto-oncogene is almost exclusively mutated at two helical domain hotpots (E542K and E545K) [43].…”