APOBEC3B: Pathological consequences of an innate immune DNA mutator

Burns, Michael B.; Leonard, Brandon; Harris, Reuben S.

doi:10.4103/2319-4170.148904

Cited by 50 publications

(29 citation statements)

References 62 publications

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“…APOBEC3B has been implicated recently as an endogenous mutagen in several cancers [(28–30) and references therein], including ovarian cancer (24). Moreover, its overexpression has been linked to poor patient outcomes in multiple cancer types (31–36) Using the Mayo cohort gene expression data and clinical information from above, we asked whether APOBEC3B affects patient outcomes in HGSOC.…”

Section: Resultsmentioning

confidence: 99%

“…For instance, AID has been linked to various B cell malignancies [reviewed in (23)]. A second prominent example is the recent finding that APOBEC3B is overexpressed and a significant source of mutation in breast, ovarian, and several other cancers [(17,24–27) and reviewed in (28–30)]. APOBEC3B deaminates cytosines in genomic DNA to produce promutagenic uracil lesions, which can result in mutations if they are not repaired faithfully.…”

Section: Introductionmentioning

confidence: 99%

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APOBEC3G Expression Correlates with T-Cell Infiltration and Improved Clinical Outcomes in High-grade Serous Ovarian Carcinoma

Leonard

Starrett

Maurer

et al. 2016

Clinical Cancer Research

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Purpose APOBEC3 DNA cytosine deaminase family members normally defend against viruses and transposons. However, deregulated APOBEC3 activity causes mutations in cancer. Due to broad expression profiles and varying mixtures of normal and cancer cells in tumors, including immune cell infiltration, it is difficult to determine where different APOBEC3s are expressed. Here, we ask whether correlations exist between APOBEC3 expression and T cell infiltration in high-grade serous ovarian cancer (HGSOC), and assess whether these correlations have prognostic value. Experimental Design Transcripts for APOBEC3G, APOBEC3B, and the T cell markers, CD3D, CD4, CD8A, GZMB, PRF1, and RNF128 were quantified by RT-qPCR for a cohort of 354 HGSOC patients. Expression values were correlated with each other and clinical parameters. Two additional cohorts were used to extend HGSOC clinical results. Immuno-imaging was used to colocalize APOBEC3G and the T cell marker CD3. TCGA data extended expression analyses to additional cancer types. Results A surprising positive correlation was found for expression of APOBEC3G and several T cell genes in HGSOC. Immunohistochemistry and immunofluorescent imaging showed protein colocalization in tumor-infiltrating T lymphocytes. High APOBEC3G expression correlated with improved outcomes in multiple HGSOC cohorts. TCGA data analyses revealed that expression of APOBEC3D and APOBEC3H also correlates with CD3D across multiple cancer types. Conclusions Our results identify APOBEC3G as a new candidate biomarker for tumor-infiltrating T lymphocytes and favorable prognoses for HGSOC. Our data also highlight the complexity of the tumor environment with respect to differential APOBEC family gene expression in both tumor and surrounding normal cell types.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

APOBEC3G Expression Correlates with T-Cell Infiltration and Improved Clinical Outcomes in High-grade Serous Ovarian Carcinoma

Leonard

Starrett

Maurer

et al. 2016

Clinical Cancer Research

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“…The collective studies suggest that the up-regulation of APOBEC3B in developing tumors promotes cancer progression [12] (Fig. 2).…”

Section: The Mutational Process Induced By Apobec3bmentioning

confidence: 99%

APOBEC3B, a molecular driver of mutagenesis in human cancers

Zou

Wang

et al. 2017

Cell Biosci

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Human cancers results in large part from the accumulation of multiple mutations. The progression of premalignant cells is an evolutionary process in which mutations provide the fundamental driving force for genetic diversity. The increased mutation rate in premalignant cells allows selection for increased proliferation and survival and ultimately leads to invasion, metastasis, recurrence, and therapeutic resistance. Therefore, it is important to understand the molecular determinants of the mutational processes. Recent genome-wide sequencing data showed that apolipoprotein B mRNA editing catalytic polypeptide-like 3B (APOBEC3B) is a key molecular driver inducing mutations in multiple human cancers. APOBEC3B, a DNA cytosine deaminase, is overexpressed in a wide spectrum of human cancers. Its overexpression and aberrant activation lead to unexpected clusters of mutations in the majority of cancers. This phenomenon of clustered mutations, termed kataegis (from the Greek word for showers), forms unique mutation signatures. In this review, we will discuss the biological function of APOBEC3B, its tumorigenic role in promoting mutational processes in cancer development and the clinical potential to develop novel therapeutics by targeting APOBEC3B.

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“…APOBECs function in innate immunity by deaminating single-stranded DNA (ssDNA) replication intermediates of viral pathogens (retro-, hepadna-, papilloma-viruses), inhibiting the retrotransposition of L1 and Alu elements and mediating the clearance of foreign DNA through deamination-dependent mechanisms (Jarmuz et al , 2002; Burns et al , 2015). In addition to these functions in normal physiology, APOBEC enzymes have also been implicated in cancer pathogenesis.…”

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confidence: 99%

Elevated APOBEC3B expression drives a kataegic-like mutation signature and replication stress-related therapeutic vulnerabilities in p53-defective cells

et al. 2017

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Background:Elevated APOBEC3B expression in tumours correlates with a kataegic pattern of localised hypermutation. We assessed the cellular phenotypes associated with high-level APOBEC3B expression and the influence of p53 status on these phenotypes using an isogenic system.Methods:We used RNA interference of p53 in cells with inducible APOBEC3B and assessed DNA damage response (DDR) biomarkers. The mutational effects of APOBEC3B were assessed using whole-genome sequencing. In vitro small-molecule inhibitor sensitivity profiling was used to identify candidate therapeutic vulnerabilities.Results:Although APOBEC3B expression increased the incorporation of genomic uracil, invoked DDR biomarkers and caused cell cycle arrest, inactivation of p53 circumvented APOBEC3B-induced cell cycle arrest without reversing the increase in genomic uracil or DDR biomarkers. The continued expression of APOBEC3B in p53-defective cells not only caused a kataegic mutational signature but also caused hypersensitivity to small-molecule DDR inhibitors (ATR, CHEK1, CHEK2, PARP, WEE1 inhibitors) as well as cisplatin/ATR inhibitor and ATR/PARP inhibitor combinations.Conclusions:Although loss of p53 might allow tumour cells to tolerate elevated APOBEC3B expression, continued expression of this enzyme might impart a number of therapeutic vulnerabilities upon tumour cells.

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APOBEC3B: Pathological consequences of an innate immune DNA mutator

Cited by 50 publications

References 62 publications

APOBEC3G Expression Correlates with T-Cell Infiltration and Improved Clinical Outcomes in High-grade Serous Ovarian Carcinoma

APOBEC3G Expression Correlates with T-Cell Infiltration and Improved Clinical Outcomes in High-grade Serous Ovarian Carcinoma

APOBEC3B, a molecular driver of mutagenesis in human cancers

Elevated APOBEC3B expression drives a kataegic-like mutation signature and replication stress-related therapeutic vulnerabilities in p53-defective cells

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