Mutator Catalogues and That the Proportion of CG Muta- Types

RESEARCH HIGHLIGHTS

carcinoma. Moreover, the authors of APOBEC3B mRNA were generally GENOMICS found that 60–90% of mutations in higher, indicating that this is the these tumours affected CG base pairs, major mutator across the 13 cancer Mutator catalogues and that the proportion of CG muta- types. Using carcinogenic mutation tions correlated with the expression catalogues (such as the Cancer Gene of APOBEC3B across cancer types. Census and COSMIC) the authors Because APOBECs target cytosines found that APOBEC-signature within specific sequence contexts, mutations were prevalent in a subset the authors examined the cytosine of genes considered to be drivers of mutation signatures and found, for cancer, indicating that APOBEC- example, that those signatures in mediated mutation may initiate bladder and cervical cancers were and/or drive carcinogenesis. similar, and were biased towards the Taking a broader approach, optimum APOBEC3B motif (which Alexandrov and colleagues sought

STOCKBYTE is TCA). The authors also found that to assess the mutational landscape bladder, cervical, head and neck, of >7,000 cancers, using exome and breast cancer, as well as lung and whole-genome sequence The sequencing of cancer genomes adenocarcinoma and lung squamous data. Their analyses revealed 21 has confirmed the complexity of cell carcinoma, all of which had distinct mutational signatures APOBEC3B is the somatic mutations that occur in the strongest APOBEC3B-specific that occurred, to different extents a mutator in tumours. However, there seem to cytosine mutation signatures, had the and in different combinations, be some patterns in the mutation highest levels of cytosine mutation across 30 cancer types. The most several types spectra, such as preference for muta- clustering. Together, these data indi- prevalent signatures involved two of cancer tion of unmethylated cytosine, which cate that APOBEC3B is a mutator in patterns of C to T substitutions are affected in a strand-coordinated several types of cancer. (which probably partially repre- and clustered (which has been called Roberts and colleagues also sent spontaneous deamination of ‘kataegis’) manner. This indicates assessed the extent to which methylcytosine); the occurrence that this subset of cytosine mutations APOBECs contribute to the muta- of these signatures correlated with is nonrandom and enzymatically tion profile of various cancers, using age, indicating a progressive accu- induced, and the APOBEC cytosine available sequencing data. These mulation of these alterations. The deaminases are thought to be respon- authors defined APOBEC-signature next most prominent signature was sible. Cytosine deamination produces mutations as those occurring in attributable to APOBEC activity; uracil, which can lead to base sub- TCA or TCT sequences in which this signature occurred in 16 types stitution mutations, either because the cytosine is mutated to guanine of cancer. These authors also found it can be a template for adenine in or thymine (which are the most that APOBEC-signature mutations DNA replication or because it can be likely to occur after the processing of occurred in clusters, which may removed to form an abasic site that is abasic sites). Of the 2,680 tumours reflect the existence of regions of then processed by error-prone DNA (comprising 14 types of cancer), single-stranded DNA, which are the polymerases. the authors found 498 APOBEC- biochemical APOBEC substrate. Because APOBEC3B was previ- signature mutation clusters Although mutagenesis is thought ously shown to be associated with affecting 13 types of cancer. Six to initiate and drive tumorigenesis, cytosine mutations in breast cancer, cancer types — bladder, cervical, a direct role for APOBEC-mediated Burns and colleagues investigated head and neck, breast and lung mutagenesis in driving this process whether this mutator is more gener- (adenocarcinoma and squamous cell has yet to be demonstrated. ally associated with cancer. These carcinoma) — showed significant Gemma K. Alderton authors analysed the gene expression presence of samples enriched with profiles of 19 types of cancer and APOBEC-signature mutations. The ORIGINAL RESEARCH PAPERS Burns, M. B., Temiz, N. A. & Harris, R. S. Evidence for found that APOBEC3B was upregu- assessment of gene expression data APOBEC3B mutagenesis in multiple human cancers. lated in tumours of the prostate, revealed that APOBEC3B, as well as Nature Genet. 45, 977–983 (2013) | Roberts, S. A. et al. An APOBEC cytidine deaminase mutagenesis cervix, skin, breast, uterus, bladder APOBEC1, APOBEC3A, APOBEC3F pattern is widespread in human cancers. Nature and of the head and neck, as well as and APOBEC3G mRNA levels sig- Genet. 45, 970–976 (2013) | Alexandrov, L. B. et al. in lung adenocarcinoma, lung squa- nificantly correlated with APOBEC- Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013) mous cell carcinoma and in renal cell signature mutations, although levels

NATURE REVIEWS | CANCER VOLUME 13 | OCTOBER 2013