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1.
Cell ; 184(6): 1650-1650.e1, 2021 03 18.
Artículo en Inglés | MEDLINE | ID: mdl-33740457

RESUMEN

Understanding how tumors grow and evolve over time is crucial to help shed light on the underlying reasons why treatments fail and tumors metastasize. This SnapShot provides a brief introduction into the main concepts of tumor evolution. To view this SnapShot, open or download the PDF.


Asunto(s)
Neoplasias/patología , Humanos , Mutación/genética , Metástasis de la Neoplasia , Neoplasias/genética
2.
Nature ; 616(7957): 543-552, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-37046093

RESUMEN

Intratumour heterogeneity (ITH) fuels lung cancer evolution, which leads to immune evasion and resistance to therapy1. Here, using paired whole-exome and RNA sequencing data, we investigate intratumour transcriptomic diversity in 354 non-small cell lung cancer tumours from 347 out of the first 421 patients prospectively recruited into the TRACERx study2,3. Analyses of 947 tumour regions, representing both primary and metastatic disease, alongside 96 tumour-adjacent normal tissue samples implicate the transcriptome as a major source of phenotypic variation. Gene expression levels and ITH relate to patterns of positive and negative selection during tumour evolution. We observe frequent copy number-independent allele-specific expression that is linked to epigenomic dysfunction. Allele-specific expression can also result in genomic-transcriptomic parallel evolution, which converges on cancer gene disruption. We extract signatures of RNA single-base substitutions and link their aetiology to the activity of the RNA-editing enzymes ADAR and APOBEC3A, thereby revealing otherwise undetected ongoing APOBEC activity in tumours. Characterizing the transcriptomes of primary-metastatic tumour pairs, we combine multiple machine-learning approaches that leverage genomic and transcriptomic variables to link metastasis-seeding potential to the evolutionary context of mutations and increased proliferation within primary tumour regions. These results highlight the interplay between the genome and transcriptome in influencing ITH, lung cancer evolution and metastasis.


Asunto(s)
Evolución Molecular , Genoma Humano , Neoplasias Pulmonares , Metástasis de la Neoplasia , Transcriptoma , Humanos , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Genómica , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Mutación , Metástasis de la Neoplasia/genética , Transcriptoma/genética , Alelos , Aprendizaje Automático , Genoma Humano/genética
3.
Nature ; 616(7957): 534-542, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-37046095

RESUMEN

Metastatic disease is responsible for the majority of cancer-related deaths1. We report the longitudinal evolutionary analysis of 126 non-small cell lung cancer (NSCLC) tumours from 421 prospectively recruited patients in TRACERx who developed metastatic disease, compared with a control cohort of 144 non-metastatic tumours. In 25% of cases, metastases diverged early, before the last clonal sweep in the primary tumour, and early divergence was enriched for patients who were smokers at the time of initial diagnosis. Simulations suggested that early metastatic divergence more frequently occurred at smaller tumour diameters (less than 8 mm). Single-region primary tumour sampling resulted in 83% of late divergence cases being misclassified as early, highlighting the importance of extensive primary tumour sampling. Polyclonal dissemination, which was associated with extrathoracic disease recurrence, was found in 32% of cases. Primary lymph node disease contributed to metastatic relapse in less than 20% of cases, representing a hallmark of metastatic potential rather than a route to subsequent recurrences/disease progression. Metastasis-seeding subclones exhibited subclonal expansions within primary tumours, probably reflecting positive selection. Our findings highlight the importance of selection in metastatic clone evolution within untreated primary tumours, the distinction between monoclonal versus polyclonal seeding in dictating site of recurrence, the limitations of current radiological screening approaches for early diverging tumours and the need to develop strategies to target metastasis-seeding subclones before relapse.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Evolución Clonal , Células Clonales , Evolución Molecular , Neoplasias Pulmonares , Metástasis de la Neoplasia , Humanos , Carcinoma de Pulmón de Células no Pequeñas/patología , Células Clonales/patología , Estudios de Cohortes , Progresión de la Enfermedad , Neoplasias Pulmonares/patología , Metástasis de la Neoplasia/diagnóstico , Metástasis de la Neoplasia/patología , Recurrencia Local de Neoplasia
4.
Nature ; 616(7957): 525-533, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-37046096

RESUMEN

Lung cancer is the leading cause of cancer-associated mortality worldwide1. Here we analysed 1,644 tumour regions sampled at surgery or during follow-up from the first 421 patients with non-small cell lung cancer prospectively enrolled into the TRACERx study. This project aims to decipher lung cancer evolution and address the primary study endpoint: determining the relationship between intratumour heterogeneity and clinical outcome. In lung adenocarcinoma, mutations in 22 out of 40 common cancer genes were under significant subclonal selection, including classical tumour initiators such as TP53 and KRAS. We defined evolutionary dependencies between drivers, mutational processes and whole genome doubling (WGD) events. Despite patients having a history of smoking, 8% of lung adenocarcinomas lacked evidence of tobacco-induced mutagenesis. These tumours also had similar detection rates for EGFR mutations and for RET, ROS1, ALK and MET oncogenic isoforms compared with tumours in never-smokers, which suggests that they have a similar aetiology and pathogenesis. Large subclonal expansions were associated with positive subclonal selection. Patients with tumours harbouring recent subclonal expansions, on the terminus of a phylogenetic branch, had significantly shorter disease-free survival. Subclonal WGD was detected in 19% of tumours, and 10% of tumours harboured multiple subclonal WGDs in parallel. Subclonal, but not truncal, WGD was associated with shorter disease-free survival. Copy number heterogeneity was associated with extrathoracic relapse within 1 year after surgery. These data demonstrate the importance of clonal expansion, WGD and copy number instability in determining the timing and patterns of relapse in non-small cell lung cancer and provide a comprehensive clinical cancer evolutionary data resource.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Adenocarcinoma del Pulmón/etiología , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/patología , Carcinoma de Pulmón de Células no Pequeñas/etiología , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/etiología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Mutación , Recurrencia Local de Neoplasia/genética , Filogenia , Resultado del Tratamiento , Fumar/genética , Fumar/fisiopatología , Mutagénesis , Variaciones en el Número de Copia de ADN
5.
Nature ; 587(7832): 126-132, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32879494

RESUMEN

Chromosomal instability in cancer consists of dynamic changes to the number and structure of chromosomes1,2. The resulting diversity in somatic copy number alterations (SCNAs) may provide the variation necessary for tumour evolution1,3,4. Here we use multi-sample phasing and SCNA analysis of 1,421 samples from 394 tumours across 22 tumour types to show that continuous chromosomal instability results in pervasive SCNA heterogeneity. Parallel evolutionary events, which cause disruption in the same genes (such as BCL9, MCL1, ARNT (also known as HIF1B), TERT and MYC) within separate subclones, were present in 37% of tumours. Most recurrent losses probably occurred before whole-genome doubling, that was found as a clonal event in 49% of tumours. However, loss of heterozygosity at the human leukocyte antigen (HLA) locus and loss of chromosome 8p to a single haploid copy recurred at substantial subclonal frequencies, even in tumours with whole-genome doubling, indicating ongoing karyotype remodelling. Focal amplifications that affected chromosomes 1q21 (which encompasses BCL9, MCL1 and ARNT), 5p15.33 (TERT), 11q13.3 (CCND1), 19q12 (CCNE1) and 8q24.1 (MYC) were frequently subclonal yet appeared to be clonal within single samples. Analysis of an independent series of 1,024 metastatic samples revealed that 13 focal SCNAs were enriched in metastatic samples, including gains in chromosome 8q24.1 (encompassing MYC) in clear cell renal cell carcinoma and chromosome 11q13.3 (encompassing CCND1) in HER2+ breast cancer. Chromosomal instability may enable the continuous selection of SCNAs, which are established as ordered events that often occur in parallel, throughout tumour evolution.


Asunto(s)
Inestabilidad Cromosómica/genética , Evolución Molecular , Cariotipo , Metástasis de la Neoplasia/genética , Neoplasias/genética , Cromosomas Humanos Par 11/genética , Cromosomas Humanos Par 8/genética , Células Clonales/metabolismo , Células Clonales/patología , Ciclina E/genética , Variaciones en el Número de Copia de ADN/genética , Femenino , Humanos , Pérdida de Heterocigocidad/genética , Masculino , Mutagénesis , Metástasis de la Neoplasia/patología , Neoplasias/patología , Proteínas Oncogénicas/genética
8.
PLoS Med ; 13(12): e1002204, 2016 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-28027312

RESUMEN

BACKGROUND: Understanding the cancer genome is seen as a key step in improving outcomes for cancer patients. Genomic assays are emerging as a possible avenue to personalised medicine in breast cancer. However, evolution of the cancer genome during the natural history of breast cancer is largely unknown, as is the profile of disease at death. We sought to study in detail these aspects of advanced breast cancers that have resulted in lethal disease. METHODS AND FINDINGS: Three patients with oestrogen-receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer and one patient with triple negative breast cancer underwent rapid autopsy as part of an institutional prospective community-based rapid autopsy program (CASCADE). Cases represented a range of management problems in breast cancer, including late relapse after early stage disease, de novo metastatic disease, discordant disease response, and disease refractory to treatment. Between 5 and 12 metastatic sites were collected at autopsy together with available primary tumours and longitudinal metastatic biopsies taken during life. Samples underwent paired tumour-normal whole exome sequencing and single nucleotide polymorphism (SNP) arrays. Subclonal architectures were inferred by jointly analysing all samples from each patient. Mutations were validated using high depth amplicon sequencing. Between cases, there were significant differences in mutational burden, driver mutations, mutational processes, and copy number variation. Within each case, we found dramatic heterogeneity in subclonal structure from primary to metastatic disease and between metastatic sites, such that no single lesion captured the breadth of disease. Metastatic cross-seeding was found in each case, and treatment drove subclonal diversification. Subclones displayed parallel evolution of treatment resistance in some cases and apparent augmentation of key oncogenic drivers as an alternative resistance mechanism. We also observed the role of mutational processes in subclonal evolution. Limitations of this study include the potential for bias introduced by joint analysis of formalin-fixed archival specimens with fresh specimens and the difficulties in resolving subclones with whole exome sequencing. Other alterations that could define subclones such as structural variants or epigenetic modifications were not assessed. CONCLUSIONS: This study highlights various mechanisms that shape the genome of metastatic breast cancer and the value of studying advanced disease in detail. Treatment drives significant genomic heterogeneity in breast cancers which has implications for disease monitoring and treatment selection in the personalised medicine paradigm.


Asunto(s)
Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Exoma , Mutación , Polimorfismo de Nucleótido Simple , Adulto , Autopsia , Investigación Participativa Basada en la Comunidad , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos
9.
Nat Commun ; 15(1): 6039, 2024 Jul 18.
Artículo en Inglés | MEDLINE | ID: mdl-39019871

RESUMEN

During each cell cycle, the process of DNA replication timing is tightly regulated to ensure the accurate duplication of the genome. The extent and significance of alterations in this process during malignant transformation have not been extensively explored. Here, we assess the impact of altered replication timing (ART) on cancer evolution by analysing replication-timing sequencing of cancer and normal cell lines and 952 whole-genome sequenced lung and breast tumours. We find that 6%-18% of the cancer genome exhibits ART, with regions with a change from early to late replication displaying an increased mutation rate and distinct mutational signatures. Whereas regions changing from late to early replication contain genes with increased expression and present a preponderance of APOBEC3-mediated mutation clusters and associated driver mutations. We demonstrate that ART occurs relatively early during cancer evolution and that ART may have a stronger correlation with mutation acquisition than alterations in chromatin structure.


Asunto(s)
Neoplasias de la Mama , Momento de Replicación del ADN , Neoplasias Pulmonares , Mutación , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Femenino , Línea Celular Tumoral , Desaminasas APOBEC/genética , Desaminasas APOBEC/metabolismo , Tasa de Mutación , Replicación del ADN/genética , Genoma Humano
10.
Nat Genet ; 56(1): 60-73, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38049664

RESUMEN

In this study, the impact of the apolipoprotein B mRNA-editing catalytic subunit-like (APOBEC) enzyme APOBEC3B (A3B) on epidermal growth factor receptor (EGFR)-driven lung cancer was assessed. A3B expression in EGFR mutant (EGFRmut) non-small-cell lung cancer (NSCLC) mouse models constrained tumorigenesis, while A3B expression in tumors treated with EGFR-targeted cancer therapy was associated with treatment resistance. Analyses of human NSCLC models treated with EGFR-targeted therapy showed upregulation of A3B and revealed therapy-induced activation of nuclear factor kappa B (NF-κB) as an inducer of A3B expression. Significantly reduced viability was observed with A3B deficiency, and A3B was required for the enrichment of APOBEC mutation signatures, in targeted therapy-treated human NSCLC preclinical models. Upregulation of A3B was confirmed in patients with NSCLC treated with EGFR-targeted therapy. This study uncovers the multifaceted roles of A3B in NSCLC and identifies A3B as a potential target for more durable responses to targeted cancer therapy.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Animales , Ratones , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Mutación , Regulación hacia Arriba/genética , Receptores ErbB/genética , Receptores ErbB/metabolismo , Citidina Desaminasa/genética , Antígenos de Histocompatibilidad Menor/genética , Antígenos de Histocompatibilidad Menor/metabolismo
11.
Nat Med ; 29(4): 833-845, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-37045996

RESUMEN

Lung adenocarcinomas (LUADs) display a broad histological spectrum from low-grade lepidic tumors through to mid-grade acinar and papillary and high-grade solid, cribriform and micropapillary tumors. How morphology reflects tumor evolution and disease progression is poorly understood. Whole-exome sequencing data generated from 805 primary tumor regions and 121 paired metastatic samples across 248 LUADs from the TRACERx 421 cohort, together with RNA-sequencing data from 463 primary tumor regions, were integrated with detailed whole-tumor and regional histopathological analysis. Tumors with predominantly high-grade patterns showed increased chromosomal complexity, with higher burden of loss of heterozygosity and subclonal somatic copy number alterations. Individual regions in predominantly high-grade pattern tumors exhibited higher proliferation and lower clonal diversity, potentially reflecting large recent subclonal expansions. Co-occurrence of truncal loss of chromosomes 3p and 3q was enriched in predominantly low-/mid-grade tumors, while purely undifferentiated solid-pattern tumors had a higher frequency of truncal arm or focal 3q gains and SMARCA4 gene alterations compared with mixed-pattern tumors with a solid component, suggesting distinct evolutionary trajectories. Clonal evolution analysis revealed that tumors tend to evolve toward higher-grade patterns. The presence of micropapillary pattern and 'tumor spread through air spaces' were associated with intrathoracic recurrence, in contrast to the presence of solid/cribriform patterns, necrosis and preoperative circulating tumor DNA detection, which were associated with extra-thoracic recurrence. These data provide insights into the relationship between LUAD morphology, the underlying evolutionary genomic landscape, and clinical and anatomical relapse risk.


Asunto(s)
Adenocarcinoma del Pulmón , Adenocarcinoma , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Adenocarcinoma/genética , Adenocarcinoma/patología , Recurrencia Local de Neoplasia/patología , Adenocarcinoma del Pulmón/genética , Progresión de la Enfermedad , ADN Helicasas , Proteínas Nucleares , Factores de Transcripción
12.
Oncogene ; 41(9): 1376-1382, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-35091677

RESUMEN

A variety of cancer entities are driven by KRAS mutations, which remain difficult to target clinically. Survival pathways, such as resistance to cell death, may represent a promising treatment approach in KRAS mutated cancers. Based on the frequently observed genomic deletions of BCL-2-related ovarian killer (BOK) in cancer patients, we explored the function of BOK in a mutant KrasG12D-driven murine model of lung cancer. Using KrasG12D/+ Bok-/- mice, we observed an overall tumor-promoting function of BOK in vivo. Specifically, loss of BOK reduced proliferation both in cell lines in vitro as well as in KrasG12D-driven tumor lesions in vivo. During tumor development in vivo, loss of BOK resulted in a lower tumor burden, with fewer, smaller, and less advanced tumors. Using KrasG12D/+ Tp53Δ/Δ Bok-/- mice, we identified that this phenotype was entirely dependent on the presence of functional p53. Furthermore, analysis of a human dataset of untreated early-stage lung tumors did not identify any common deletion of the BOK locus, independently of the TP53 status or the histopathological classification. Taken together our data indicate that BOK supports tumor progression in Kras-driven lung cancer.


Asunto(s)
Proteína p53 Supresora de Tumor
13.
Cancer Discov ; 11(10): 2456-2473, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-33947663

RESUMEN

APOBEC3 enzymes are cytosine deaminases implicated in cancer. Precisely when APOBEC3 expression is induced during cancer development remains to be defined. Here we show that specific APOBEC3 genes are upregulated in breast ductal carcinoma in situ, 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 G1 phase of the cell cycle. Analysis of TRACERx NSCLC clinical samples and mouse lung cancer models revealed APOBEC3B 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 APOBEC3 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.This article is highlighted in the In This Issue feature, p. 2355.


Asunto(s)
Desaminasas APOBEC/genética , Neoplasias de la Mama/genética , Carcinoma Ductal/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/genética , Animales , Línea Celular Tumoral , Inestabilidad Cromosómica , Replicación del ADN , Femenino , Humanos , Ratones
14.
Nat Genet ; 52(3): 283-293, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-32139907

RESUMEN

Whole-genome doubling (WGD) is a prevalent event in cancer, involving a doubling of the entire chromosome complement. However, despite its prevalence and prognostic relevance, the evolutionary selection pressures for WGD in cancer have not been investigated. Here, we combine evolutionary simulations with an analysis of cancer sequencing data to explore WGD during cancer evolution. Simulations suggest that WGD can be selected to mitigate the irreversible, ratchet-like, accumulation of deleterious somatic alterations, provided that they occur at a sufficiently high rate. Consistent with this, we observe an enrichment for WGD in tumor types with extensive loss of heterozygosity, including lung squamous cell carcinoma and triple-negative breast cancers, and we find evidence for negative selection against homozygous loss of essential genes before, but not after, WGD. Finally, we demonstrate that loss of heterozygosity and temporal dissection of mutations can be exploited to identify novel tumor suppressor genes and to obtain a deeper characterization of known cancer genes.


Asunto(s)
Adenocarcinoma del Pulmón/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Células Escamosas/genética , Duplicación de Gen , Genoma Humano/genética , Neoplasias Pulmonares/genética , Proteínas Supresoras de Tumor/genética , Estudios de Cohortes , Simulación por Computador , Variaciones en el Número de Copia de ADN , Evolución Molecular , Humanos , Estudios Longitudinales , Pérdida de Heterocigocidad , Mutación , Estudios Prospectivos
15.
Nat Commun ; 11(1): 4527, 2020 09 10.
Artículo en Inglés | MEDLINE | ID: mdl-32913197

RESUMEN

Evasion of programmed cell death represents a critical form of oncogene addiction in cancer cells. Understanding the molecular mechanisms underpinning cancer cell survival despite the oncogenic stress could provide a molecular basis for potential therapeutic interventions. Here we explore the role of pro-survival genes in cancer cell integrity during clonal evolution in non-small cell lung cancer (NSCLC). We identify gains of MCL-1 at high frequency in multiple independent NSCLC cohorts, occurring both clonally and subclonally. Clonal loss of functional TP53 is significantly associated with subclonal gains of MCL-1. In mice, tumour progression is delayed upon pharmacologic or genetic inhibition of MCL-1. These findings reveal that MCL-1 gains occur with high frequency in lung adenocarcinoma and can be targeted therapeutically.


Asunto(s)
Antineoplásicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/genética , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/genética , Animales , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Apoptosis/genética , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico por imagen , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Evolución Clonal , Variaciones en el Número de Copia de ADN , Conjuntos de Datos como Asunto , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Humanos , Pulmón/diagnóstico por imagen , Pulmón/patología , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Ratones , Ratones Transgénicos , Mutación , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/antagonistas & inhibidores , Cultivo Primario de Células , Estudios Prospectivos , Proteínas Proto-Oncogénicas p21(ras)/genética , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , RNA-Seq , Estudios Retrospectivos , Esferoides Celulares , Tiofenos/farmacología , Tiofenos/uso terapéutico , Carga Tumoral/efectos de los fármacos , Carga Tumoral/genética , Proteína p53 Supresora de Tumor/genética , Microtomografía por Rayos X
16.
Genome Biol ; 17(1): 185, 2016 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-27634334

RESUMEN

BACKGROUND: The APOBEC3 family of cytidine deaminases mutate the cancer genome in a range of cancer types. Although many studies have documented the downstream effects of APOBEC3 activity through next-generation sequencing, less is known about their upstream regulation. In this study, we sought to identify a molecular basis for APOBEC3 expression and activation. RESULTS: HER2 amplification and PTEN loss promote DNA replication stress and APOBEC3B activity in vitro and correlate with APOBEC3 mutagenesis in vivo. HER2-enriched breast carcinomas display evidence of elevated levels of replication stress-associated DNA damage in vivo. Chemical and cytotoxic induction of replication stress, through aphidicolin, gemcitabine, camptothecin or hydroxyurea exposure, activates transcription of APOBEC3B via an ATR/Chk1-dependent pathway in vitro. APOBEC3B activation can be attenuated through repression of oncogenic signalling, small molecule inhibition of receptor tyrosine kinase signalling and alleviation of replication stress through nucleoside supplementation. CONCLUSION: These data link oncogene, loss of tumour suppressor gene and drug-induced replication stress with APOBEC3B activity, providing new insights into how cytidine deaminase-induced mutagenesis might be activated in tumourigenesis and limited therapeutically.


Asunto(s)
Neoplasias de la Mama/genética , Citosina Desaminasa/genética , Replicación del ADN , Familia de Multigenes , Mutagénesis , Estrés Fisiológico , Desaminasas APOBEC , Antineoplásicos/farmacología , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Biomarcadores de Tumor , Neoplasias de la Mama/metabolismo , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Citidina Desaminasa , Citosina Desaminasa/metabolismo , Daño del ADN , Replicación del ADN/efectos de los fármacos , Activación Enzimática , Femenino , Amplificación de Genes , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Humanos , Mutación , Oncogenes , Transducción de Señal , Estrés Fisiológico/efectos de los fármacos
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