Scientific Literature for APOBEC in Cancer

Scientific Literature for APOBEC in Cancer


1) Discovery of APOBEC mutagenesis in cancer

Burns, M.B., et al. (Harris Lab) APOBEC3B is an enzymatic source of mutation in breast cancer. Nature 494, 366-70 (2013). [link]

News Highlights: Alderton, G.K. Genome instability – DNA transitions. Nature Reviews Cancer 13, 220-1 (2013); Hartsough, M.M. A DNA deaminase drives mutagenesis in breast cancer. Cancer Discovery 3, OF23 (2013)

Significance: 1st paper to report a role for APOBEC3B-catalyzed DNA deamination in breast cancer.

Nik-Zainal, S., et al. (Stratton Lab; Breast Cancer Working Group of the International Cancer Genome Consortium) Mutational processes molding the genomes of 21 breast cancers. Cell 149, 979-93 (2012). [link]

Significance: Full genome sequences for 21 breast cancers, which revealed several distinct mutational patterns including both dispersed and clustered cytosine mutations consistent with with APOBEC mutagenesis (clustered mutations coined ‘kataegis’ due to similarity to localized thundershowers).


2) Broadening discovery of APOBEC mutagenesis in cancer

Burns, M.B., et al. (Harris Lab) Evidence for APOBEC3B mutagenesis in multiple human cancers. Nature Genetics 45, 977-83 (2013). [link]

News Highlights: Razzak, M. APOBEC – a double-edged sword. Nature Reviews Clinical Oncology 10, 488 (2013). Wong, J. Virus-fighting protein causes mutations in cancers. The Lancet Oncology 14, e347 (2013). Kuong, K.J. & Loeb, L. APOBEC3B mutagenesis in cancer. Nature Genetics 45, 964-65 (2013). Alderton, G.K. Genomics: Mutator catalogues. Nature Reviews Cancer 13, 681 (2013).

Significance: A systematic analysis of mutation patterns and deaminase expression levels in 19 different tumors converging upon APOBEC3B-catalyzed genomic DNA deamination as a general mechanism of cancer mutagenesis (especially in lung, head/neck, cervical, bladder, and breast cancers).

Roberts, S.A., et al. (Gordenin Lab) An APOBEC cytidine deaminase mutagenesis pattern is widespread in human cancers. Nature Genetics 45, 970-6 (2013). [link]

Significance: A bioinformatic analysis of mutation patterns across cancer converging upon APOBEC mutagenesis as a common source of mutation in many cancers (especially in lung, head/neck, cervical, bladder, and breast cancers).

Alexandrov, L.B., et al. (Stratton Lab) Signatures of mutational processes in human cancer. Nature 500, 415-21 (2013). [link]

Significance: The most comprehensive analysis of mutational patterns in cancer to-date finding evidence for APOBEC mutagenesis in 16/30 cancers and estimating that APOBEC is the 2nd largest source of mutation in cancer. 

Leonard, B., et al. (Harris Lab) APOBEC3B upregulation and genomic mutation patterns in serous ovarian carcinoma. Cancer Research 73, 7222-31 (2013). [link]

Significance: 1st paper to implicate APOBEC3B mutagenesis in ovarian cancer.

Henderson, S., et al. (Fenton Lab) APOBEC-mediated cytosine deamination links PIK3CA helical domain mutations to human papillomavirus-driven tumor development. Cell Reports 7, 1833-41 (2014). [link]

Significance: This paper is the 1st to implicate APOBEC mutagenesis in causing PIK3CA activation (i.e. creating a common cancer ‘driver’ mutation). It is also one of several papers in 2014 linking HPV infection to APOBEC upregulation and cancer mutagenesis.

de Bruin, E.C., et al. (Swanton Lab) Spatial and temporal diversity in genomic instability processes defines lung cancer evolution. Science 346, 251-6 (2014). [link]

Significance: This paper is the first to clearly show that APOBEC is a dominant source of mutation during primary tumor outgrowth into metastases. It also links APOBEC mutagenesis to the generation of driver mutations.


3) Publications demonstrating clinical impact

Sieuwerts, A.M., et al. (Martens Lab) Elevated APOBEC3B correlates with poor outcomes for ER-positive breast cancers. Hormones & Cancer 5, 405-13 (2014). [link]

Significance: This manuscript is the first to report an association between high APOBEC3B levels and negative clinical outcomes including disease-free survival, metastasis-free survival, and importantly overall survival.


4) APOBEC inhibitor development

Li, M., et al. (Harris & Harki Labs) First-in-class small molecule inhibitors of the single-strand DNA cytosine deaminase APOBEC3G. ACS Chemical Biology 7, 506-17 (2012). [link]

Significance: This paper describes first-in-class A3G inhibitors (1st for any polynucleotide deaminase), a novel mechanism of active site encroachment, and a 1.4Å A3G catalytic domain crystal structure (highest resolution to-date).

Olson, M.E., et al. (Harki & Harris Labs) Small molecule APOBEC3G DNA cytosine deaminase inhibitors based on a 4-amino-1,2,4-triazole-3-thiol scaffold. ChemMedChem 8, 112-7 (2013). [link]

Significance: This paper reports a second chemotype that inhibits APOBEC3G through a covalent mechanism (Featured on Journal Cover).


5) Recent reviews on APOBEC mutagenesis in cancer

Harris, R.S. Cancer mutation signatures, DNA damage mechanisms, and potential clinical implications. Genome Medicine 5, 87 (3 pages) (2013). [link]

Roberts, S.A. & Gordenin, D.A. Hypermutation in human cancer genomes: footprints and mechanisms. Nature Reviews Cancer 14, 786-800 (2014). [link]

Harris, R.S. Molecular mechanism and clinical impact of APOBEC3B-catalyzed mutagenesis in breast cancer. Breast Cancer Research, in press (2014).


6) Additional recent papers of importance to the field

Petersen-Mahrt*, S.K., Harris*, R.S., Neuberger, M.S. AID mutates E. coli suggesting a DNA deamination mechanism for antibody diversification. Nature 418, 99-103 (2002). (* equal contributions). [link]

Significance: 1st paper to demonstrate DNA cytosine deamination activity for any protein, and 1st to propose the now textbook DNA deamination model for AID-mediated antibody gene diversification.

Harris*, R.S., Petersen-Mahrt*, S.K., Neuberger, M.S. RNA editing protein APOBEC1 and some of its homologues can act as DNA mutators. Molecular Cell 10, 1247-53 (2002). (* equal contributions). [link]

Significance: Discovery of the DNA cytosine deaminase activity of APOBEC1 and APOBEC3 enzymes and implication that this is a defining feature of a larger family of enzymes (also the 1st study to implicate APOBEC3 over-expression in multiple human cancers including breast cancer).

Chen*, K.-M., Harjes*, E., Gross*, P.J., et al. (Harris & Matsuo Labs) Structure of the DNA deaminase domain of the HIV-1 restriction factor APOBEC3G. Nature 452, 116-119 (2008) (* equal contributions). [link]

Significance: 1st high-resolution structure of the DNA deaminase domain of APOBEC3G, and the 1st structure for any DNA deaminase family member.