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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 -
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 -
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 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 -
Nature Biotechnology Jan 2021Current base editors (BEs) catalyze only base transitions (C to T and A to G) and cannot produce base transversions. Here we present BEs that cause C-to-A transversions...
Current base editors (BEs) catalyze only base transitions (C to T and A to G) and cannot produce base transversions. Here we present BEs that cause C-to-A transversions in Escherichia coli and C-to-G transversions in mammalian cells. These glycosylase base editors (GBEs) consist of a Cas9 nickase, a cytidine deaminase and a uracil-DNA glycosylase (Ung). Ung excises the U base created by the deaminase, forming an apurinic/apyrimidinic (AP) site that initiates the DNA repair process. In E. coli, we used activation-induced cytidine deaminase (AID) to construct AID-nCas9-Ung and found that it converts C to A with an average editing specificity of 93.8% ± 4.8% and editing efficiency of 87.2% ± 6.9%. For use in mammalian cells, we replaced AID with rat APOBEC1 (APOBEC-nCas9-Ung). We tested APOBEC-nCas9-Ung at 30 endogenous sites, and we observed C-to-G conversions with a high editing specificity at the sixth position of the protospacer between 29.7% and 92.2% and an editing efficiency between 5.3% and 53.0%. APOBEC-nCas9-Ung supplements the current adenine and cytidine BEs (ABE and CBE, respectively) and could be used to target G/C disease-causing mutations.
Topics: APOBEC-1 Deaminase; Adenine; Animals; Base Pairing; CRISPR-Associated Protein 9; CRISPR-Cas Systems; Cytidine Deaminase; Cytosine; DNA Glycosylases; DNA Repair; Deoxyribonuclease I; Escherichia coli; Gene Editing; Guanine; Rats; Uracil-DNA Glycosidase
PubMed: 32690970
DOI: 10.1038/s41587-020-0592-2 -
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 -
Science (New York, N.Y.) Oct 2020The extent of somatic mutation and clonal selection in the human bladder remains unknown. We sequenced 2097 bladder microbiopsies from 20 individuals using targeted ( =...
The extent of somatic mutation and clonal selection in the human bladder remains unknown. We sequenced 2097 bladder microbiopsies from 20 individuals using targeted ( = 1914 microbiopsies), whole-exome ( = 655), and whole-genome ( = 88) sequencing. We found widespread positive selection in 17 genes. Chromatin remodeling genes were frequently mutated, whereas mutations were absent in several major bladder cancer genes. There was extensive interindividual variation in selection, with different driver genes dominating the clonal landscape across individuals. Mutational signatures were heterogeneous across clones and individuals, which suggests differential exposure to mutagens in the urine. Evidence of APOBEC mutagenesis was found in 22% of the microbiopsies. Sequencing multiple microbiopsies from five patients with bladder cancer enabled comparisons with cancer-free individuals and across histological features. This study reveals a rich landscape of mutational processes and selection in normal urothelium with large heterogeneity across clones and individuals.
Topics: APOBEC Deaminases; Adult; Aged; Biopsy; Chromatin Assembly and Disassembly; Female; Genes, Neoplasm; Humans; Male; Middle Aged; Mutagenesis; Mutagens; Mutation; Selection, Genetic; Urinary Bladder; Urinary Bladder Neoplasms; Urothelium
PubMed: 33004514
DOI: 10.1126/science.aba8347 -
Nature Genetics Nov 2021Esophageal squamous cell carcinoma (ESCC) shows remarkable variation in incidence that is not fully explained by known lifestyle and environmental risk factors. It has...
Esophageal squamous cell carcinoma (ESCC) shows remarkable variation in incidence that is not fully explained by known lifestyle and environmental risk factors. It has been speculated that an unknown exogenous exposure(s) could be responsible. Here we combine the fields of mutational signature analysis with cancer epidemiology to study 552 ESCC genomes from eight countries with varying incidence rates. Mutational profiles were similar across all countries studied. Associations between specific mutational signatures and ESCC risk factors were identified for tobacco, alcohol, opium and germline variants, with modest impacts on mutation burden. We find no evidence of a mutational signature indicative of an exogenous exposure capable of explaining differences in ESCC incidence. Apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like (APOBEC)-associated mutational signatures single-base substitution (SBS)2 and SBS13 were present in 88% and 91% of cases, respectively, and accounted for 25% of the mutation burden on average, indicating that APOBEC activation is a crucial step in ESCC tumor development.
Topics: APOBEC Deaminases; Adult; Aged; Aged, 80 and over; Aldehyde Dehydrogenase, Mitochondrial; Brazil; China; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Female; Humans; Incidence; Iran; Male; Middle Aged; Mutation; Tumor Suppressor Protein p53; United Kingdom; Whole Genome Sequencing
PubMed: 34663923
DOI: 10.1038/s41588-021-00928-6 -
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