APOBEC3B mutagenesis in cancer: basic mechanisms and clinical implications
Session type: Parallel sessions
Cancer genomic DNA sequences enable identification of all mutations and suggest targets for precision medicine. The identities and patterns of the mutations themselves also provide critical information for deducing the originating DNA damaging agents, causal molecular mechanisms, and thus additional therapeutic targets. A classic example is ultraviolet light, which crosslinks adjacent pyrimidines and causes C-to-T transitions. A new example is the DNA cytosine deaminase APOBEC3B, which was identified recently as a source of DNA damage and mutagenesis in breast and several additional cancer types. This enzyme is normally an effector protein in the innate immune response to virus infection but its upregulation in breast cancer causes elevated levels of genomic C-to-U deamination events, which manifest as C-to-T transitions and C-to-G transversions within distinct DNA trinucleotide contexts (preferentially 5'-TCA and 5'-TCG). Genomic C-to-U deamination events within the same trinucleotide contexts also lead to cytosine mutation clusters (kataegis), and may precipitate visible chromosomal aberrations such as translocations. Clinical studies indicate that APOBEC3B upregulation correlates with poorer outcomes for oestrogen receptor positive breast cancer patients including shorter durations of disease free survival and overall survival after surgery. APOBEC3B may therefore have both diagnostic and prognostic potential. APOBEC3B may also be a candidate for therapeutic targeting because inhibition of this non-essential enzyme is predicted to decrease tumour mutation rates and diminish the likelihood of undesirable mutation-dependent outcomes such as recurrence, metastasis, and the development of therapy resistant tumours.
1. Burns MB, Lackey L, Carpenter MA, Rathore A, Land AM, Leonard B, Refsland EW, Kotandeniya D, Tretyakova N, Nikas JB, Yee D, Temiz NA, Donohue DE, McDougle RM, Brown WL, Law EK, Harris RS. APOBEC3B is an enzymatic source of mutation in breast cancer. Nature 2013;494:366-370.
2. Burns MB, Temiz NA, Harris RS. Evidence for APOBEC3B mutagenesis in multiple human cancers. Nature Genetics 2013;45:977-83.
3. Harris RS. Cancer mutation signatures, DNA damage mechanisms, and potential clinical implications. Genome Medicine 2013;5:87-89.
4. Sieuwerts AM, Willis S, Burns MB, Look MP, Meijer-Van Gelder ME, Schlicker A, Heidemann RM, Jacobs H, Wessels L, Leyland-Jones B, Gray K, Foekens JA, Harris RS, Martens JWM. Elevated APOBEC3B correlates with poor outcomes for ER-positive breast cancers. Hormones & Cancer 2014, in press.