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Cancer Letters Jan 2021Cervical cancer is one of the foremost common cancers in women. Human papillomavirus (HPV) infection remains a major risk factor of cervical cancer. In addition,... (Review)
Review
Cervical cancer is one of the foremost common cancers in women. Human papillomavirus (HPV) infection remains a major risk factor of cervical cancer. In addition, numerous other genetic and epigenetic factors also are involved in the underlying pathogenesis of cervical cancer. Recently, it has been reported that apolipoprotein B mRNA editing enzyme catalytic polypeptide like (APOBEC), DNA-editing protein plays an important role in the molecular pathogenesis of cancer. Particularly, the APOBEC3 family was shown to induce tumor mutations by aberrant DNA editing mechanism. In general, APOBEC3 enzymes play a pivotal role in the deamination of cytidine to uridine in DNA and RNA to control diverse biological processes such as regulation of protein expression, innate immunity, and embryonic development. Innate antiviral activity of the APOBEC3 family members restrict retroviruses, endogenous retro-element, and DNA viruses including the HPV that is the leading risk factor for cervical cancer. This review briefly describes the pathogenesis of cervical cancer and discusses in detail the recent findings on the role of APOBEC in the molecular pathogenesis of cervical cancer.
Topics: APOBEC Deaminases; Animals; Female; Humans; Immunity, Innate; Uterine Cervical Neoplasms
PubMed: 33038491
DOI: 10.1016/j.canlet.2020.10.004 -
Cell Nov 2020The integration of mass spectrometry-based proteomics with next-generation DNA and RNA sequencing profiles tumors more comprehensively. Here this "proteogenomics"...
The integration of mass spectrometry-based proteomics with next-generation DNA and RNA sequencing profiles tumors more comprehensively. Here this "proteogenomics" approach was applied to 122 treatment-naive primary breast cancers accrued to preserve post-translational modifications, including protein phosphorylation and acetylation. Proteogenomics challenged standard breast cancer diagnoses, provided detailed analysis of the ERBB2 amplicon, defined tumor subsets that could benefit from immune checkpoint therapy, and allowed more accurate assessment of Rb status for prediction of CDK4/6 inhibitor responsiveness. Phosphoproteomics profiles uncovered novel associations between tumor suppressor loss and targetable kinases. Acetylproteome analysis highlighted acetylation on key nuclear proteins involved in the DNA damage response and revealed cross-talk between cytoplasmic and mitochondrial acetylation and metabolism. Our results underscore the potential of proteogenomics for clinical investigation of breast cancer through more accurate annotation of targetable pathways and biological features of this remarkably heterogeneous malignancy.
Topics: APOBEC Deaminases; Adult; Aged; Aged, 80 and over; Breast Neoplasms; Carcinogenesis; Cohort Studies; DNA Damage; DNA Repair; Female; Humans; Immunotherapy; Metabolomics; Middle Aged; Molecular Targeted Therapy; Mutagenesis; Phosphorylation; Protein Kinase Inhibitors; Protein Kinases; Proteogenomics; Receptor, ErbB-2; Retinoblastoma Protein; Tumor Microenvironment
PubMed: 33212010
DOI: 10.1016/j.cell.2020.10.036 -
Nature Aug 2023Acquired drug resistance to anticancer targeted therapies remains an unsolved clinical problem. Although many drivers of acquired drug resistance have been identified,...
Acquired drug resistance to anticancer targeted therapies remains an unsolved clinical problem. Although many drivers of acquired drug resistance have been identified, the underlying molecular mechanisms shaping tumour evolution during treatment are incompletely understood. Genomic profiling of patient tumours has implicated apolipoprotein B messenger RNA editing catalytic polypeptide-like (APOBEC) cytidine deaminases in tumour evolution; however, their role during therapy and the development of acquired drug resistance is undefined. Here we report that lung cancer targeted therapies commonly used in the clinic can induce cytidine deaminase APOBEC3A (A3A), leading to sustained mutagenesis in drug-tolerant cancer cells persisting during therapy. Therapy-induced A3A promotes the formation of double-strand DNA breaks, increasing genomic instability in drug-tolerant persisters. Deletion of A3A reduces APOBEC mutations and structural variations in persister cells and delays the development of drug resistance. APOBEC mutational signatures are enriched in tumours from patients with lung cancer who progressed after extended responses to targeted therapies. This study shows that induction of A3A in response to targeted therapies drives evolution of drug-tolerant persister cells, suggesting that suppression of A3A expression or activity may represent a potential therapeutic strategy in the prevention or delay of acquired resistance to lung cancer targeted therapy.
Topics: Humans; Cytidine Deaminase; DNA Breaks, Double-Stranded; Genomic Instability; Lung Neoplasms; Molecular Targeted Therapy; Mutation; Drug Resistance, Neoplasm
PubMed: 37407818
DOI: 10.1038/s41586-023-06303-1 -
Nature Jun 2023Metastatic cancer remains an almost inevitably lethal disease. A better understanding of disease progression and response to therapies therefore remains of utmost... (Comparative Study)
Comparative Study
Metastatic cancer remains an almost inevitably lethal disease. A better understanding of disease progression and response to therapies therefore remains of utmost importance. Here we characterize the genomic differences between early-stage untreated primary tumours and late-stage treated metastatic tumours using a harmonized pan-cancer analysis (or reanalysis) of two unpaired primary and metastatic cohorts of 7,108 whole-genome-sequenced tumours. Metastatic tumours in general have a lower intratumour heterogeneity and a conserved karyotype, displaying only a modest increase in mutations, although frequencies of structural variants are elevated overall. Furthermore, highly variable tumour-specific contributions of mutational footprints of endogenous (for example, SBS1 and APOBEC) and exogenous mutational processes (for example, platinum treatment) are present. The majority of cancer types had either moderate genomic differences (for example, lung adenocarcinoma) or highly consistent genomic portraits (for example, ovarian serous carcinoma) when comparing early-stage and late-stage disease. Breast, prostate, thyroid and kidney renal clear cell carcinomas and pancreatic neuroendocrine tumours are clear exceptions to the rule, displaying an extensive transformation of their genomic landscape in advanced stages. Exposure to treatment further scars the tumour genome and introduces an evolutionary bottleneck that selects for known therapy-resistant drivers in approximately half of treated patients. Our data showcase the potential of pan-cancer whole-genome analysis to identify distinctive features of late-stage tumours and provide a valuable resource to further investigate the biological basis of cancer and resistance to therapies.
Topics: Female; Humans; Male; Disease Progression; Genomics; Mutation; Neoplasm Metastasis; Neoplasms; Genome, Human; Cohort Studies; Karyotyping; APOBEC Deaminases
PubMed: 37165194
DOI: 10.1038/s41586-023-06054-z -
Viruses Feb 2021The APOBEC family of DNA cytosine deaminases provides a broad and overlapping defense against viral infections. Successful viral pathogens, by definition, have evolved... (Review)
Review
The APOBEC family of DNA cytosine deaminases provides a broad and overlapping defense against viral infections. Successful viral pathogens, by definition, have evolved strategies to escape restriction by the APOBEC enzymes of their hosts. HIV-1 and related retroviruses are thought to be the predominant natural substrates of APOBEC enzymes due to obligate single-stranded DNA replication intermediates, abundant evidence for cDNA strand C-to-U editing (genomic strand G-to-A hypermutation), and a potent APOBEC degradation mechanism. In contrast, much lower mutation rates are observed in double-stranded DNA herpesviruses and the evidence for APOBEC mutation has been less compelling. However, recent work has revealed that Epstein-Barr virus (EBV), Kaposi's sarcoma herpesvirus (KSHV), and herpes simplex virus-1 (HSV-1) are potential substrates for cellular APOBEC enzymes. To prevent APOBEC-mediated restriction these viruses have repurposed their ribonucleotide reductase (RNR) large subunits to directly bind, inhibit, and relocalize at least two distinct APOBEC enzymes - APOBEC3B and APOBEC3A. The importance of this interaction is evidenced by genetic inactivation of the EBV RNR (BORF2), which results in lower viral infectivity and higher levels of C/G-to-T/A hypermutation. This RNR-mediated mechanism therefore likely functions to protect lytic phase viral DNA replication intermediates from APOBEC-catalyzed DNA C-to-U deamination. The RNR-APOBEC interaction defines a new host-pathogen conflict that the virus must win in real-time for transmission and pathogenesis. However, partial losses over evolutionary time may also benefit the virus by providing mutational fuel for adaptation.
Topics: APOBEC Deaminases; Animals; DNA Replication; DNA Viruses; DNA, Viral; Herpesviridae; Herpesviridae Infections; Host-Pathogen Interactions; Humans; Virus Replication
PubMed: 33671095
DOI: 10.3390/v13030390 -
Nature Feb 2022Clustered somatic mutations are common in cancer genomes and previous analyses reveal several types of clustered single-base substitutions, which include doublet- and...
Clustered somatic mutations are common in cancer genomes and previous analyses reveal several types of clustered single-base substitutions, which include doublet- and multi-base substitutions, diffuse hypermutation termed omikli, and longer strand-coordinated events termed kataegis. Here we provide a comprehensive characterization of clustered substitutions and clustered small insertions and deletions (indels) across 2,583 whole-genome-sequenced cancers from 30 types of cancer. Clustered mutations were highly enriched in driver genes and associated with differential gene expression and changes in overall survival. Several distinct mutational processes gave rise to clustered indels, including signatures that were enriched in tobacco smokers and homologous-recombination-deficient cancers. Doublet-base substitutions were caused by at least 12 mutational processes, whereas most multi-base substitutions were generated by either tobacco smoking or exposure to ultraviolet light. Omikli events, which have previously been attributed to APOBEC3 activity, accounted for a large proportion of clustered substitutions; however, only 16.2% of omikli matched APOBEC3 patterns. Kataegis was generated by multiple mutational processes, and 76.1% of all kataegic events exhibited mutational patterns that are associated with the activation-induced deaminase (AID) and APOBEC3 family of deaminases. Co-occurrence of APOBEC3 kataegis and extrachromosomal DNA (ecDNA), termed kyklonas (Greek for cyclone), was found in 31% of samples with ecDNA. Multiple distinct kyklonic events were observed on most mutated ecDNA. ecDNA containing known cancer genes exhibited both positive selection and kyklonic hypermutation. Our results reveal the diversity of clustered mutational processes in human cancer and the role of APOBEC3 in recurrently mutating and fuelling the evolution of ecDNA.
Topics: APOBEC Deaminases; Genome; Humans; INDEL Mutation; Mutagenesis; Mutation; Neoplasms
PubMed: 35140399
DOI: 10.1038/s41586-022-04398-6 -
Nature Methods Dec 2019N-methyladenosine (mA) is a widespread RNA modification that influences nearly every aspect of the messenger RNA lifecycle. Our understanding of mA has been facilitated...
N-methyladenosine (mA) is a widespread RNA modification that influences nearly every aspect of the messenger RNA lifecycle. Our understanding of mA has been facilitated by the development of global mA mapping methods, which use antibodies to immunoprecipitate methylated RNA. However, these methods have several limitations, including high input RNA requirements and cross-reactivity to other RNA modifications. Here, we present DART-seq (deamination adjacent to RNA modification targets), an antibody-free method for detecting mA sites. In DART-seq, the cytidine deaminase APOBEC1 is fused to the mA-binding YTH domain. APOBEC1-YTH expression in cells induces C-to-U deamination at sites adjacent to mA residues, which are detected using standard RNA-seq. DART-seq identifies thousands of mA sites in cells from as little as 10 ng of total RNA and can detect mA accumulation in cells over time. Additionally, we use long-read DART-seq to gain insights into mA distribution along the length of individual transcripts.
Topics: APOBEC-1 Deaminase; Adenosine; Base Sequence; Deamination; HEK293 Cells; Humans; Transcriptome
PubMed: 31548708
DOI: 10.1038/s41592-019-0570-0 -
Nature Jul 2022The APOBEC3 family of cytosine deaminases has been implicated in some of the most prevalent mutational signatures in cancer. However, a causal link between endogenous...
The APOBEC3 family of cytosine deaminases has been implicated in some of the most prevalent mutational signatures in cancer. However, a causal link between endogenous APOBEC3 enzymes and mutational signatures in human cancer genomes has not been established, leaving the mechanisms of APOBEC3 mutagenesis poorly understood. Here, to investigate the mechanisms of APOBEC3 mutagenesis, we deleted implicated genes from human cancer cell lines that naturally generate APOBEC3-associated mutational signatures over time. Analysis of non-clustered and clustered signatures across whole-genome sequences from 251 breast, bladder and lymphoma cancer cell line clones revealed that APOBEC3A deletion diminished APOBEC3-associated mutational signatures. Deletion of both APOBEC3A and APOBEC3B further decreased APOBEC3 mutation burdens, without eliminating them. Deletion of APOBEC3B increased APOBEC3A protein levels, activity and APOBEC3A-mediated mutagenesis in some cell lines. The uracil glycosylase UNG was required for APOBEC3-mediated transversions, whereas the loss of the translesion polymerase REV1 decreased overall mutation burdens. Together, these data represent direct evidence that endogenous APOBEC3 deaminases generate prevalent mutational signatures in human cancer cells. Our results identify APOBEC3A as the main driver of these mutations, indicate that APOBEC3B can restrain APOBEC3A-dependent mutagenesis while contributing its own smaller mutation burdens and dissect mechanisms that translate APOBEC3 activities into distinct mutational signatures.
Topics: APOBEC Deaminases; Cell Line, Tumor; DNA-Directed DNA Polymerase; Gene Deletion; Genome, Human; Humans; Mutagenesis; Neoplasms; Uracil-DNA Glycosidase
PubMed: 35859169
DOI: 10.1038/s41586-022-04972-y -
Cancer Discovery Oct 2021APOBEC3 enzymes are cytosine deaminases implicated in cancer. Precisely when expression is induced during cancer development remains to be defined. Here we show that...
APOBEC3 enzymes are cytosine deaminases implicated in cancer. Precisely when expression is induced during cancer development remains to be defined. Here we show that specific genes are upregulated in breast ductal carcinoma , and in preinvasive lung cancer lesions coincident with cellular proliferation. We observe evidence of APOBEC3-mediated subclonal mutagenesis propagated from TRACERx preinvasive to invasive non-small cell lung cancer (NSCLC) lesions. We find that APOBEC3B exacerbates DNA replication stress and chromosomal instability through incomplete replication of genomic DNA, manifested by accumulation of mitotic ultrafine bridges and 53BP1 nuclear bodies in the G phase of the cell cycle. Analysis of TRACERx NSCLC clinical samples and mouse lung cancer models revealed expression driving replication stress and chromosome missegregation. We propose that APOBEC3 is functionally implicated in the onset of chromosomal instability and somatic mutational heterogeneity in preinvasive disease, providing fuel for selection early in cancer evolution. SIGNIFICANCE: This study reveals the dynamics and drivers of gene expression in preinvasive disease and the exacerbation of cellular diversity by APOBEC3B through DNA replication stress to promote chromosomal instability early in cancer evolution..
Topics: APOBEC Deaminases; Animals; Breast Neoplasms; Carcinoma, Ductal; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Chromosomal Instability; DNA Replication; Female; Humans; Lung Neoplasms; Mice
PubMed: 33947663
DOI: 10.1158/2159-8290.CD-20-0725 -
DNA Repair Oct 2020The APOBEC family of cytidine deaminases has been proposed to represent a major enzymatic source of mutations in cancer. Here, we summarize available evidence that links... (Review)
Review
The APOBEC family of cytidine deaminases has been proposed to represent a major enzymatic source of mutations in cancer. Here, we summarize available evidence that links APOBEC deaminases to cancer mutagenesis. We also highlight newly identified human cell models of APOBEC mutagenesis, including cancer cell lines with suspected endogenous APOBEC activity and a cell system of telomere crisis-associated mutations. Finally, we draw on recent data to propose potential causes of APOBEC misregulation in cancer, including the instigating factors, the relevant mutator(s), and the mechanisms underlying generation of the genome-dispersed and clustered APOBEC-induced mutations.
Topics: APOBEC Deaminases; Animals; Humans; Mutagenesis; Mutation; Neoplasms
PubMed: 32818816
DOI: 10.1016/j.dnarep.2020.102905