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1.
Nat Commun ; 10(1): 2198, 2019 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-31097696

RESUMO

Many gene fusions are reported in tumours and for most their role remains unknown. As fusions are used for diagnostic and prognostic purposes, and are targets for treatment, it is crucial to assess their function in cancer. To systematically investigate the role of fusions in tumour cell fitness, we utilized RNA-sequencing data from 1011 human cancer cell lines to functionally link 8354 fusion events with genomic data, sensitivity to >350 anti-cancer drugs and CRISPR-Cas9 loss-of-fitness effects. Established clinically-relevant fusions were identified. Overall, detection of functional fusions was rare, including those involving cancer driver genes, suggesting that many fusions are dispensable for tumour fitness. Therapeutically actionable fusions involving RAF1, BRD4 and ROS1 were verified in new histologies. In addition, recurrent YAP1-MAML2 fusions were identified as activators of Hippo-pathway signaling in multiple cancer types. Our approach discriminates functional fusions, identifying new drivers of carcinogenesis and fusions that could have clinical implications.


Assuntos
Biomarcadores Tumorais/genética , Sistemas CRISPR-Cas/genética , Fusão Gênica/genética , Neoplasias/genética , Antineoplásicos/farmacologia , Carcinogênese/genética , Linhagem Celular Tumoral , Conjuntos de Dados como Assunto , Resistencia a Medicamentos Antineoplásicos/genética , Detecção Precoce de Câncer/métodos , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias/diagnóstico , Análise de Sequência de RNA
2.
Nature ; 568(7753): 511-516, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30971826

RESUMO

Functional genomics approaches can overcome limitations-such as the lack of identification of robust targets and poor clinical efficacy-that hamper cancer drug development. Here we performed genome-scale CRISPR-Cas9 screens in 324 human cancer cell lines from 30 cancer types and developed a data-driven framework to prioritize candidates for cancer therapeutics. We integrated cell fitness effects with genomic biomarkers and target tractability for drug development to systematically prioritize new targets in defined tissues and genotypes. We verified one of our most promising dependencies, the Werner syndrome ATP-dependent helicase, as a synthetic lethal target in tumours from multiple cancer types with microsatellite instability. Our analysis provides a resource of cancer dependencies, generates a framework to prioritize cancer drug targets and suggests specific new targets. The principles described in this study can inform the initial stages of drug development by contributing to a new, diverse and more effective portfolio of cancer drug targets.

3.
Cell ; 176(6): 1282-1294.e20, 2019 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-30849372

RESUMO

Multiple signatures of somatic mutations have been identified in cancer genomes. Exome sequences of 1,001 human cancer cell lines and 577 xenografts revealed most common mutational signatures, indicating past activity of the underlying processes, usually in appropriate cancer types. To investigate ongoing patterns of mutational-signature generation, cell lines were cultured for extended periods and subsequently DNA sequenced. Signatures of discontinued exposures, including tobacco smoke and ultraviolet light, were not generated in vitro. Signatures of normal and defective DNA repair and replication continued to be generated at roughly stable mutation rates. Signatures of APOBEC cytidine deaminase DNA-editing exhibited substantial fluctuations in mutation rate over time with episodic bursts of mutations. The initiating factors for the bursts are unclear, although retrotransposon mobilization may contribute. The examined cell lines constitute a resource of live experimental models of mutational processes, which potentially retain patterns of activity and regulation operative in primary human cancers.

4.
Genome Biol ; 20(1): 27, 2019 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-30722791

RESUMO

BACKGROUND: CRISPR-Cas9 genome editing is widely used to study gene function, from basic biology to biomedical research. Structural rearrangements are a ubiquitous feature of cancer cells and their impact on the functional consequences of CRISPR-Cas9 gene-editing has not yet been assessed. RESULTS: Utilizing CRISPR-Cas9 knockout screens for 250 cancer cell lines, we demonstrate that targeting structurally rearranged regions, in particular tandem or interspersed amplifications, is highly detrimental to cellular fitness in a gene-independent manner. In contrast, amplifications caused by whole chromosomal duplication have little to no impact on fitness. This effect is cell line specific and dependent on the ploidy status. We devise a copy-number ratio metric that substantially improves the detection of gene-independent cell fitness effects in CRISPR-Cas9 screens. Furthermore, we develop a computational tool, called Crispy, to account for these effects on a single sample basis and provide corrected gene fitness effects. CONCLUSION: Our analysis demonstrates the importance of structural rearrangements in mediating the effect of CRISPR-Cas9-induced DNA damage, with implications for the use of CRISPR-Cas9 gene-editing in cancer cells.


Assuntos
Sistemas CRISPR-Cas , Variação Estrutural do Genoma , Genômica/métodos , Sequenciamento Completo do Genoma , Linhagem Celular Tumoral , Humanos , Neoplasias/genética , Ploidias , Software
5.
Genome Res ; 29(3): 464-471, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30674557

RESUMO

Genome-wide CRISPR/Cas9 knockout screens are revolutionizing mammalian functional genomics. However, their range of applications remains limited by signal variability from different guide RNAs that target the same gene, which confounds gene effect estimation and dictates large experiment sizes. To address this problem, we report JACKS, a Bayesian method that jointly analyzes screens performed with the same guide RNA library. Modeling the variable guide efficacies greatly improves hit identification over processing a single screen at a time and outperforms existing methods. This more efficient analysis gives additional hits and allows designing libraries with a 2.5-fold reduction in required cell numbers without sacrificing performance compared to current analysis standards.


Assuntos
Sistemas CRISPR-Cas , Técnicas de Inativação de Genes/métodos , Software , Animais , Teorema de Bayes
6.
iScience ; 2018 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-30553813

RESUMO

CellMinerCDB provides a web-based resource (https://discover.nci.nih.gov/cellminercdb/) for integrating multiple forms of pharmacological and genomic analyses, and unifying the richest cancer cell line datasets (the NCI-60, NCI-SCLC, Sanger/MGH GDSC, and Broad CCLE/CTRP). CellMinerCDB enables data queries for genomics and gene regulatory network analyses, and exploration of pharmacogenomic determinants and drug signatures. It leverages overlaps of cell lines and drugs across databases to examine reproducibility and expand pathway analyses. We illustrate the value of CellMinerCDB for elucidating gene expression determinants, such as DNA methylation and copy number variations, and highlight complexities in assessing mutational burden. We demonstrate the value of CellMinerCDB in selecting drugs with reproducible activity, expand on the dominant role of SLFN11 for drug response, and present novel response determinants and genomic signatures for topoisomerase inhibitors and schweinfurthins. We also introduce LIX1L as a gene associated with mesenchymal signature and regulation of cellular migration and invasiveness.

7.
Nat Rev Drug Discov ; 2018 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-30310233

RESUMO

Given the high attrition rates, substantial costs and slow pace of new drug discovery and development, repurposing of 'old' drugs to treat both common and rare diseases is increasingly becoming an attractive proposition because it involves the use of de-risked compounds, with potentially lower overall development costs and shorter development timelines. Various data-driven and experimental approaches have been suggested for the identification of repurposable drug candidates; however, there are also major technological and regulatory challenges that need to be addressed. In this Review, we present approaches used for drug repurposing (also known as drug repositioning), discuss the challenges faced by the repurposing community and recommend innovative ways by which these challenges could be addressed to help realize the full potential of drug repurposing.

8.
Nat Commun ; 9(1): 3385, 2018 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-30139972

RESUMO

Patients with seemingly the same tumour can respond very differently to treatment. There are strong, well-established effects of somatic mutations on drug efficacy, but there is at-most anecdotal evidence of a germline component to drug response. Here, we report a systematic survey of how inherited germline variants affect drug susceptibility in cancer cell lines. We develop a joint analysis approach that leverages both germline and somatic variants, before applying it to screening data from 993 cell lines and 265 drugs. Surprisingly, we find that the germline contribution to variation in drug susceptibility can be as large or larger than effects due to somatic mutations. Several of the associations identified have a direct relationship to the drug target. Finally, using 17-AAG response as an example, we show how germline effects in combination with transcriptomic data can be leveraged for improved patient stratification and to identify new markers for drug sensitivity.

9.
BMC Genomics ; 19(1): 604, 2018 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-30103702

RESUMO

BACKGROUND: Genome editing by CRISPR-Cas9 technology allows large-scale screening of gene essentiality in cancer. A confounding factor when interpreting CRISPR-Cas9 screens is the high false-positive rate in detecting essential genes within copy number amplified regions of the genome. We have developed the computational tool CRISPRcleanR which is capable of identifying and correcting gene-independent responses to CRISPR-Cas9 targeting. CRISPRcleanR uses an unsupervised approach based on the segmentation of single-guide RNA fold change values across the genome, without making any assumption about the copy number status of the targeted genes. RESULTS: Applying our method to existing and newly generated genome-wide essentiality profiles from 15 cancer cell lines, we demonstrate that CRISPRcleanR reduces false positives when calling essential genes, correcting biases within and outside of amplified regions, while maintaining true positive rates. Established cancer dependencies and essentiality signals of amplified cancer driver genes are detectable post-correction. CRISPRcleanR reports sgRNA fold changes and normalised read counts, is therefore compatible with downstream analysis tools, and works with multiple sgRNA libraries. CONCLUSIONS: CRISPRcleanR is a versatile open-source tool for the analysis of CRISPR-Cas9 knockout screens to identify essential genes.


Assuntos
Sistemas CRISPR-Cas , Marcação de Genes/métodos , Genoma Humano , Neoplasias/genética , Linhagem Celular Tumoral , Variações do Número de Cópias de DNA , Amplificação de Genes , Técnicas de Inativação de Genes/métodos , Genes Essenciais , Ensaios de Triagem em Larga Escala , Humanos , Análise de Sequência de DNA , Software
10.
Sci Rep ; 8(1): 6713, 2018 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-29713020

RESUMO

Cancer hallmarks are evolutionary traits required by a tumour to develop. While extensively characterised, the way these traits are achieved through the accumulation of somatic mutations in key biological pathways is not fully understood. To shed light on this subject, we characterised the landscape of pathway alterations associated with somatic mutations observed in 4,415 patients across ten cancer types, using 374 orthogonal pathway gene-sets mapped onto canonical cancer hallmarks. Towards this end, we developed SLAPenrich: a computational method based on population-level statistics, freely available as an open source R package. Assembling the identified pathway alterations into sets of hallmark signatures allowed us to connect somatic mutations to clinically interpretable cancer mechanisms. Further, we explored the heterogeneity of these signatures, in terms of ratio of altered pathways associated with each individual hallmark, assuming that this is reflective of the extent of selective advantage provided to the cancer type under consideration. Our analysis revealed the predominance of certain hallmarks in specific cancer types, thus suggesting different evolutionary trajectories across cancer lineages. Finally, although many pathway alteration enrichments are guided by somatic mutations in frequently altered high-confidence cancer genes, excluding these driver mutations preserves the hallmark heterogeneity signatures, thus the detected hallmarks' predominance across cancer types. As a consequence, we propose the hallmark signatures as a ground truth to characterise tails of infrequent genomic alterations and identify potential novel cancer driver genes and networks.

11.
Elife ; 72018 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-29345617

RESUMO

Malignant mesothelioma (MM) is poorly responsive to systemic cytotoxic chemotherapy and invariably fatal. Here we describe a screen of 94 drugs in 15 exome-sequenced MM lines and the discovery of a subset defined by loss of function of the nuclear deubiquitinase BRCA associated protein-1 (BAP1) that demonstrate heightened sensitivity to TRAIL (tumour necrosis factor-related apoptosis-inducing ligand). This association is observed across human early passage MM cultures, mouse xenografts and human tumour explants. We demonstrate that BAP1 deubiquitinase activity and its association with ASXL1 to form the Polycomb repressive deubiquitinase complex (PR-DUB) impacts TRAIL sensitivity implicating transcriptional modulation as an underlying mechanism. Death receptor agonists are well-tolerated anti-cancer agents demonstrating limited therapeutic benefit in trials without a targeting biomarker. We identify BAP1 loss-of-function mutations, which are frequent in MM, as a potential genomic stratification tool for TRAIL sensitivity with immediate and actionable therapeutic implications.


Assuntos
Neoplasias Pulmonares/fisiopatologia , Mesotelioma/fisiopatologia , Proteínas Repressoras/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina Tiolesterase/metabolismo , Animais , Linhagem Celular Tumoral , Humanos , Camundongos
12.
Cancer Res ; 78(3): 769-780, 2018 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-29229604

RESUMO

Transcriptional dysregulation induced by aberrant transcription factors (TF) is a key feature of cancer, but its global influence on drug sensitivity has not been examined. Here, we infer the transcriptional activity of 127 TFs through analysis of RNA-seq gene expression data newly generated for 448 cancer cell lines, combined with publicly available datasets to survey a total of 1,056 cancer cell lines and 9,250 primary tumors. Predicted TF activities are supported by their agreement with independent shRNA essentiality profiles and homozygous gene deletions, and recapitulate mutant-specific mechanisms of transcriptional dysregulation in cancer. By analyzing cell line responses to 265 compounds, we uncovered numerous TFs whose activity interacts with anticancer drugs. Importantly, combining existing pharmacogenomic markers with TF activities often improves the stratification of cell lines in response to drug treatment. Our results, which can be queried freely at dorothea.opentargets.io, offer a broad foundation for discovering opportunities to refine personalized cancer therapies.Significance: Systematic analysis of transcriptional dysregulation in cancer cell lines and patient tumor specimens offers a publicly searchable foundation to discover new opportunities to refine personalized cancer therapies. Cancer Res; 78(3); 769-80. ©2017 AACR.

13.
Bioinformatics ; 34(7): 1226-1228, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29186349

RESUMO

Motivation: Large pharmacogenomic screenings integrate heterogeneous cancer genomic datasets as well as anti-cancer drug responses on thousand human cancer cell lines. Mining this data to identify new therapies for cancer sub-populations would benefit from common data structures, modular computational biology tools and user-friendly interfaces. Results: We have developed GDSCTools: a software aimed at the identification of clinically relevant genomic markers of drug response. The Genomics of Drug Sensitivity in Cancer (GDSC) database (www.cancerRxgene.org) integrates heterogeneous cancer genomic datasets as well as anti-cancer drug responses on a thousand cancer cell lines. Including statistical tools (analysis of variance) and predictive methods (Elastic Net), as well as common data structures, GDSCTools allows users to reproduce published results from GDSC and to implement new analytical methods. In addition, non-GDSC data resources can also be analysed since drug responses and genomic features can be encoded as CSV files. Contact: thomas.cokelaer@pasteur.fr or saezrodriguez.rwth-aachen.de or mg12@sanger.ac.uk. Supplementary information: Supplementary data are available at Bioinformatics online.

14.
Clin Cancer Res ; 24(1): 84-94, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-29061644

RESUMO

Purpose: Despite intense research, treatment options for patients with mesothelioma are limited and offer only modest survival advantage. We screened a large panel of compounds in multiple mesothelioma models and correlated sensitivity with a range of molecular features to detect biomarkers of drug response.Experimental design: We utilized a high-throughput chemical inhibitor screen in a panel of 889 cancer cell lines, including both immortalized and primary early-passage mesothelioma lines, alongside comprehensive molecular characterization using Illumina whole-exome sequencing, copy-number analysis and Affymetrix array whole transcriptome profiling. Subsequent validation was done using functional assays such as siRNA silencing and mesothelioma mouse xenograft models.Results: A subgroup of immortalized and primary MPM lines appeared highly sensitive to FGFR inhibition. None of these lines harbored genomic alterations of FGFR family members, but rather BAP1 protein loss was associated with enhanced sensitivity to FGFR inhibition. This was confirmed in an MPM mouse xenograft model and by BAP1 knockdown and overexpression in cell line models. Gene expression analyses revealed an association between BAP1 loss and increased expression of the receptors FGFR1/3 and ligands FGF9/18. BAP1 loss was associated with activation of MAPK signaling. These associations were confirmed in a cohort of MPM patient samples.Conclusions: A subgroup of mesotheliomas cell lines harbor sensitivity to FGFR inhibition. BAP1 protein loss enriches for this subgroup and could serve as a potential biomarker to select patients for FGFR inhibitor treatment. These data identify a clinically relevant MPM subgroup for consideration of FGFR therapeutics in future clinical studies. Clin Cancer Res; 24(1); 84-94. ©2017 AACR.

15.
J Thorac Dis ; 9(10): 3719-3727, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29268379

RESUMO

Background: Red blood cell (RBC) transfusion is a well-known predictor of acute kidney injury (AKI) and death after cardiac surgery. This study aimed to define the relationship between age and the need for RBC. Methods: Study population included 1,765 consecutive patients undergoing on-pump procedures from 2013 to 2015. The relationship between RBC transfusion and both survival and AKI, and any interaction with age was estimated. A propensity score for the likelihood to receive RBC transfusion was calculated using multivariate logistic regression analysis to adjust for the effect of confounding factors. A logistic estimation curve was developed to investigate the interaction between this score and age. Results: Patients receiving RBC transfusions had more comorbidities irrespective of age. Elderly patients underwent transfusion more often than younger patients with a 1.3-fold increase in the relative risk for transfusion. Age did not independently predict the need for RBC. AKI and mortality rates were significantly higher in transfused subsets irrespective of age. Conclusions: Comorbidity profile and not age per se confers an increased risk of transfusion.

16.
Genome Res ; 27(4): 613-625, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28179366

RESUMO

Drug resistance is an almost inevitable consequence of cancer therapy and ultimately proves fatal for the majority of patients. In many cases, this is the consequence of specific gene mutations that have the potential to be targeted to resensitize the tumor. The ability to uniformly saturate the genome with point mutations without chromosome or nucleotide sequence context bias would open the door to identify all putative drug resistance mutations in cancer models. Here, we describe such a method for elucidating drug resistance mechanisms using genome-wide chemical mutagenesis allied to next-generation sequencing. We show that chemically mutagenizing the genome of cancer cells dramatically increases the number of drug-resistant clones and allows the detection of both known and novel drug resistance mutations. We used an efficient computational process that allows for the rapid identification of involved pathways and druggable targets. Such a priori knowledge would greatly empower serial monitoring strategies for drug resistance in the clinic as well as the development of trials for drug-resistant patients.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Genoma Humano , Acúmulo de Mutações , Taxa de Mutação , Linhagem Celular Tumoral , Humanos , Modelos Genéticos , Mutação Puntual
17.
BMC Bioinformatics ; 17(1): 542, 2016 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-27998275

RESUMO

BACKGROUND: Networks are popular and powerful tools to describe and model biological processes. Many computational methods have been developed to infer biological networks from literature, high-throughput experiments, and combinations of both. Additionally, a wide range of tools has been developed to map experimental data onto reference biological networks, in order to extract meaningful modules. Many of these methods assess results' significance against null distributions of randomized networks. However, these standard unconstrained randomizations do not preserve the functional characterization of the nodes in the reference networks (i.e. their degrees and connection signs), hence including potential biases in the assessment. RESULTS: Building on our previous work about rewiring bipartite networks, we propose a method for rewiring any type of unweighted networks. In particular we formally demonstrate that the problem of rewiring a signed and directed network preserving its functional connectivity (F-rewiring) reduces to the problem of rewiring two induced bipartite networks. Additionally, we reformulate the lower bound to the iterations' number of the switching-algorithm to make it suitable for the F-rewiring of networks of any size. Finally, we present BiRewire3, an open-source Bioconductor package enabling the F-rewiring of any type of unweighted network. We illustrate its application to a case study about the identification of modules from gene expression data mapped on protein interaction networks, and a second one focused on building logic models from more complex signed-directed reference signaling networks and phosphoproteomic data. CONCLUSIONS: BiRewire3 it is freely available at https://www.bioconductor.org/packages/BiRewire/ , and it should have a broad application as it allows an efficient and analytically derived statistical assessment of results from any network biology tool.


Assuntos
Biologia Computacional/métodos , Modelos Biológicos , Algoritmos , Interpretação Estatística de Dados , Redes Reguladoras de Genes , Humanos , Mapas de Interação de Proteínas , Distribuição Aleatória , Software
18.
Sci Rep ; 6: 36812, 2016 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-27876821

RESUMO

Mining large datasets using machine learning approaches often leads to models that are hard to interpret and not amenable to the generation of hypotheses that can be experimentally tested. We present 'Logic Optimization for Binary Input to Continuous Output' (LOBICO), a computational approach that infers small and easily interpretable logic models of binary input features that explain a continuous output variable. Applying LOBICO to a large cancer cell line panel, we find that logic combinations of multiple mutations are more predictive of drug response than single gene predictors. Importantly, we show that the use of the continuous information leads to robust and more accurate logic models. LOBICO implements the ability to uncover logic models around predefined operating points in terms of sensitivity and specificity. As such, it represents an important step towards practical application of interpretable logic models.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Algoritmos , Linhagem Celular Tumoral , Mineração de Dados/métodos , Humanos , Lógica , Modelos Teóricos , Medicina de Precisão/métodos , Sensibilidade e Especificidade
19.
Cell Rep ; 17(4): 1193-1205, 2016 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-27760321

RESUMO

Acute myeloid leukemia (AML) is an aggressive cancer with a poor prognosis, for which mainstream treatments have not changed for decades. To identify additional therapeutic targets in AML, we optimize a genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) screening platform and use it to identify genetic vulnerabilities in AML cells. We identify 492 AML-specific cell-essential genes, including several established therapeutic targets such as DOT1L, BCL2, and MEN1, and many other genes including clinically actionable candidates. We validate selected genes using genetic and pharmacological inhibition, and chose KAT2A as a candidate for downstream study. KAT2A inhibition demonstrated anti-AML activity by inducing myeloid differentiation and apoptosis, and suppressed the growth of primary human AMLs of diverse genotypes while sparing normal hemopoietic stem-progenitor cells. Our results propose that KAT2A inhibition should be investigated as a therapeutic strategy in AML and provide a large number of genetic vulnerabilities of this leukemia that can be pursued in downstream studies.


Assuntos
Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , Testes Genéticos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Terapia de Alvo Molecular , Adulto , Apoptose , Diferenciação Celular , Linhagem Celular Tumoral , Proliferação de Células , Histona Acetiltransferases/antagonistas & inibidores , Histona Acetiltransferases/metabolismo , Humanos , Reprodutibilidade dos Testes
20.
Eur J Radiol Open ; 3: 191-4, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27508212

RESUMO

Kommerell's diverticulum (KD) is defined as a bulbous dilatation of the origin of an aberrant subclavian artery due to a remnant of the left fourth aortic arch. We report the case of an asymptomatic woman in whom progressive thrombosis of the KD extending to the prevertebral tract of an aberrant right subclavian artery was detected at multidetector computed tomography imaging for lung cancer staging performed before and after the beginning of chemotherapy. Reversed blood flow in the ipsilateral vertebral artery due to subclavian steal phenomenon was also observed by color Doppler ultrasound examination.

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