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1.
Hum Mol Genet ; 23(4): 878-88, 2014 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-24070870

RESUMO

Gene amplification is a common phenomenon in malignant neoplasms of all types. One mechanism behind increased gene copy number is the formation of ring chromosomes. Such structures are mitotically unstable and during tumor progression they accumulate material from many different parts of the genome. Hence, their content varies considerably between and within tumors. Partly due to this extensive variation, the genetic content of many ring-containing tumors remains poorly characterized. Ring chromosomes are particularly prevalent in specific subtypes of sarcoma. Here, we have combined fluorescence in situ hybridization (FISH), global genomic copy number and gene expression data on ring-containing soft tissue sarcomas and show that they harbor two fundamentally different types of ring chromosome: MDM2-positive and MDM2-negative rings. While the former are often found in an otherwise normal chromosome complement, the latter seem to arise in the context of general chromosomal instability. In line with this, sarcomas with MDM2-negative rings commonly show complete loss of either CDKN2A or RB1 -both known to be important for genome integrity. Sarcomas with MDM2-positive rings instead show co-amplification of a variety of potential driver oncogenes. More than 100 different genes were found to be involved, many of which are known to induce cell growth, promote proliferation or inhibit apoptosis. Several of the amplified and overexpressed genes constitute potential drug targets.


Assuntos
Cromossomos em Anel , Sarcoma/genética , Neoplasias de Tecidos Moles/genética , Transcriptoma , Adulto , Idoso , Idoso de 80 Anos ou mais , Quinase 4 Dependente de Ciclina/genética , Feminino , Amplificação de Genes , Perfilação da Expressão Gênica , Estudos de Associação Genética , Genoma Humano , Proteína HMGA2/genética , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proteína do Retinoblastoma/genética , Sarcoma/metabolismo , Sarcoma/mortalidade , Neoplasias de Tecidos Moles/metabolismo , Neoplasias de Tecidos Moles/mortalidade
2.
Lab Invest ; 95(9): 1071-6, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26121314

RESUMO

Benign fibrous histiocytomas (FH) can be subdivided into several morphological and clinical subgroups. Recently, gene fusions involving either one of two protein kinase C genes (PRKCB and PRKCD) or the ALK gene were described in FH. We here wanted to evaluate the frequency of PRKCB and PRKCD gene fusions in FH. Using interphase fluorescence in situ hybridization on sections from formalin-fixed paraffin-embedded (FFPE) tumors, 36 cases could be analyzed. PRKCB or PRKCD rearrangements were seen in five tumors: 1/7 regular, 0/3 aneurysmal, 0/6 cellular, 2/7 epithelioid, 0/1 atypical, 2/10 deep, and 0/2 metastatic lesions. We also evaluated the status of the ALK gene in selected cases, finding rearrangements in 3/7 epithelioid and 0/1 atypical lesions. To assess the gene fusion status of FH further, deep sequencing of RNA (RNA-Seq) was performed on FFPE tissue from eight cases with unknown gene fusion status, as well as on two FH and six soft tissue sarcomas with known gene fusions; of the latter eight positive controls, the expected fusion transcript was found in all but one, while 2/8 FH with unknown genetic status showed fusion transcripts, including a novel KIRREL/PRKCA chimera. Thus, also a third member of the PRKC family is involved in FH tumorigenesis. We conclude that gene fusions involving PRKC genes occur in several morphological (regular, cellular, aneurysmal, epithelioid) and clinical (cutaneous, deep) subsets of FH, but they seem to account for only a minority of the cases. In epithelioid lesions, however, rearrangements of PRKC or ALK were seen, as mutually exclusive events, in the majority (5/7) of cases. Finally, the study also shows that RNA-Seq is a promising tool for identifying gene fusions in FFPE tissues.


Assuntos
Fusão Gênica/genética , Rearranjo Gênico/genética , Histiocitoma Fibroso Benigno/patologia , Proteína Quinase C beta/genética , Proteína Quinase C-delta/genética , Receptores Proteína Tirosina Quinases/genética , Sarcoma/patologia , Quinase do Linfoma Anaplásico , Primers do DNA/genética , Formaldeído , Histiocitoma Fibroso Benigno/genética , Técnicas Histológicas , Humanos , Hibridização in Situ Fluorescente/métodos , Proteína Quinase C beta/metabolismo , Proteína Quinase C-delta/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sarcoma/genética , Análise de Sequência de RNA/métodos , Fixação de Tecidos
3.
Lab Invest ; 95(6): 603-9, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25867764

RESUMO

Gene fusions are neoplasia-associated mutations arising from structural chromosomal rearrangements. They have a strong impact on tumor development and constitute important diagnostic markers. Malignant soft tissue tumors (sarcomas) constitute a heterogeneous group of neoplasms with >50 distinct subtypes, each of which is rare. In addition, there is considerable morphologic overlap between sarcomas and benign lesions. Several subtypes display distinct gene fusions, serving as excellent biomarkers. The development of methods for deep sequencing of the complete transcriptome (RNA-Seq) has substantially improved the possibilities for detecting gene fusions. With the aim of identifying new gene fusions of biological and clinical relevance, eight sarcomas with simple karyotypes, ie, only one or a few structural rearrangements, were subjected to massively parallel paired-end sequencing of mRNA. Three different algorithms were used to identify fusion transcripts from RNA-Seq data. Three novel (KIAA2026-NUDT11, CCBL1-ARL1, and AFF3-PHF1) and two previously known fusions (FUS-CREB3L2 and HAS2-PLAG1) were found and could be verified by other methods. These findings show that RNA-Seq is a powerful tool for detecting gene fusions in sarcomas but also suggest that it is advisable to use more than one algorithm to analyze the output data as only two of the confirmed fusions were reported by more than one of the gene fusion detection software programs. For all of the confirmed gene fusions, at least one of the genes mapped to a chromosome band implicated by the karyotype, suggesting that sarcomas with simple karyotypes constitute an excellent resource for identifying novel gene fusions.


Assuntos
Fusão Gênica/genética , Proteínas de Fusão Oncogênica/genética , RNA Mensageiro/análise , Sarcoma/genética , Análise de Sequência de RNA/métodos , Adulto , Feminino , Humanos , RNA Mensageiro/genética
4.
J Pathol ; 232(5): 534-40, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24374978

RESUMO

Pseudomyogenic haemangioendothelioma (PHE) is an intermediate malignant vascular soft tissue tumour primarily affecting children and young adults. The molecular basis of this neoplasm is unknown. We here used chromosome banding analysis, fluorescence in situ hybridization (FISH), mRNA sequencing, RT-PCR and quantitative real-time PCR on a series of morphologically well-characterized PHEs to show that a balanced translocation, t(7;19)(q22;q13), detected as the sole cytogenetic aberration in two cases, results in fusion of the SERPINE1 and FOSB genes. This translocation has not been observed in any other bone or soft tissue tumour. Interphase FISH on sections from eight additional PHEs identified the same SERPINE1-FOSB fusion in all cases. The role of SERPINE1, which is highly expressed in vascular cells, in this gene fusion is probably to provide a strong promoter for FOSB, which was found to be expressed at higher levels in PHEs than in other soft tissue tumours. FOSB encodes a transcription factor belonging to the FOS family of proteins, which, together with members of the JUN family of transcription factors, are major components of the activating protein 1 (AP-1) complex. Further studies are needed to understand the cellular impact of the aberrant expression of the FOSB gene, but as the t(7;19) resulting in the SERPINE1-FOSB fusion seems to be pathognomonic for PHE, FISH or RT-PCR could be useful for differential diagnostic purposes.


Assuntos
Neoplasias Ósseas/genética , Regulação Neoplásica da Expressão Gênica , Fusão Gênica , Hemangioendotelioma Epitelioide/genética , Inibidor 1 de Ativador de Plasminogênio/genética , Proteínas Proto-Oncogênicas c-fos/genética , Neoplasias de Tecidos Moles/genética , Transcrição Gênica , Adolescente , Neoplasias Ósseas/enzimologia , Neoplasias Ósseas/patologia , Bandeamento Cromossômico , Cromossomos Humanos Par 22 , Cromossomos Humanos Par 7 , Feminino , Testes Genéticos/métodos , Hemangioendotelioma Epitelioide/enzimologia , Hemangioendotelioma Epitelioide/patologia , Humanos , Hibridização in Situ Fluorescente , Masculino , Valor Preditivo dos Testes , RNA Mensageiro/análise , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sequência de RNA , Neoplasias de Tecidos Moles/enzimologia , Neoplasias de Tecidos Moles/patologia , Translocação Genética , Regulação para Cima
5.
Histopathology ; 64(1): 151-62, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24320890

RESUMO

Chromosomal rearrangements resulting in the fusion of coding parts from two genes or in the exchange of regulatory sequences are present in approximately 20% of all human neoplasms. More than 1000 such gene fusions have now been described, with close to 100 of them in soft tissue tumours. Although little is still known about the functional outcome of many of these gene fusions, it is well established that most of them have a major impact on tumorigenesis. Furthermore, the strong association between type of gene fusion and morphological subtype makes them highly useful diagnostic markers. Until recently, the vast majority of gene fusions were identified through molecular cytogenetic characterization of rearrangements detected at chromosome banding analysis, followed by use of the reverse transcriptase-polymerase chain reaction (RT-PCR) and Sanger sequencing. With the advent of next-generation sequencing (NGS) technologies, notably of whole transcriptomes or all poly-A(+) mRNA molecules, the possibility of detecting new gene fusions has increased dramatically. Already, a large number of novel gene fusions have been identified through NGS approaches and it can be predicted that these technologies soon will become standard diagnostic clinical tools.


Assuntos
Técnicas Genéticas , Proteínas de Fusão Oncogênica/análise , Proteínas de Fusão Oncogênica/genética , Sarcoma/genética , Rearranjo Gênico , Humanos
6.
Genes Chromosomes Cancer ; 52(10): 873-86, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23761323

RESUMO

Solitary fibrous tumor (SFT) is a mesenchymal neoplasm displaying variable morphologic and clinical features. To identify pathogenetically important genetic rearrangements, 44 SFTs were analyzed using a variety of techniques. Chromosome banding and fluorescence in situ hybridization (FISH) showed recurrent breakpoints in 12q13, clustering near the NAB2 and STAT6 genes, and single nucleotide polymorphism array analysis disclosed frequent deletions affecting STAT6. Quantitative real-time PCR revealed high expression levels of the 5'-end of NAB2 and the 3'-end of STAT6, which at deep sequencing of enriched DNA corresponded to NAB2/STAT6 fusions. Subsequent reverse-transcriptase PCR (RT-PCR) analysis identified a NAB2/STAT6 fusion in 37/41 cases, confirming that this fusion gene underlies the pathogenesis of SFT. The hypothesis that the NAB2/STAT6 fusions will result in altered properties of the transcriptional co-repressor NAB2--a key regulator of the early growth response 1 (EGR1) transcription factor - was corroborated by global gene expression analysis; SFTs showed deregulated expression of EGR1 target genes, as well as of other, developmentally important genes. We also identified several nonrandom secondary changes, notably loss of material from 13q and 14q. As neither chromosome banding nor FISH analysis identify more than a minor fraction of the fusion-positive cases, and because multiple primer combinations are required to identify all possible fusion transcripts by RT-PCR, alternative diagnostic markers might instead be found among deregulated genes identified at global gene expression analysis. Indeed, using immunohistochemistry on tissue microarrays, the top up-regulated gene, GRIA2, was found to be differentially expressed also at the protein level.


Assuntos
Proteínas de Fusão Oncogênica/genética , Proteínas Repressoras/genética , Fator de Transcrição STAT6/genética , Tumores Fibrosos Solitários/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Polimorfismo de Nucleotídeo Único , Transcriptoma , Adulto Jovem
7.
Oncotarget ; 6(40): 42793-802, 2015 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-26544893

RESUMO

PURPOSE: To investigate the genetic and epigenetic landscape of hypodiploid (<45 chromosomes) acute lymphoblastic leukemia (ALL). METHODS: Single nucleotide polymorphism array, whole exome sequencing, RNA sequencing, and methylation array analyses were performed on eleven hypodiploid ALL cases. RESULTS: In line with previous studies, mutations in IKZF3 and FLT3 were detected in near-haploid (25-30 chromosomes) cases. Low hypodiploidy (31-39 chromosomes) was associated with somatic TP53 mutations. Notably, mutations of this gene were also found in 3/3 high hypodiploid (40-44 chromosomes) cases, suggesting that the mutational patterns are similar in low hypodiploid and high hypodiploid ALL. The high hypodiploid ALLs frequently displayed substantial cell-to-cell variability in chromosomal content, indicative of chromosomal instability; a rare phenomenon in ALL. Gene expression analysis showed that genes on heterodisomic chromosomes were more highly expressed in hypodiploid cases. Cases clustered according to hypodiploid subtype in the unsupervised methylation analyses, but there was no association between chromosomal copy number and methylation levels. A comparison between samples obtained at diagnosis and relapse showed that the relapse did not arise from the major diagnostic clone in 3/4 cases. CONCLUSIONS: Taken together, our data support the conclusion that near-haploid and low hypodiploid ALL are different with regard to mutational profiles and also suggest that ALL cases with high hypodiploidy may harbor chromosomal instability.


Assuntos
Aneuploidia , Epigênese Genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Transcriptoma/genética , Cariótipo Anormal , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Hibridização in Situ Fluorescente , Lactente , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Reação em Cadeia da Polimerase Via Transcriptase Reversa
8.
Clin Cancer Res ; 21(4): 864-9, 2015 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-25516889

RESUMO

PURPOSE: Undifferentiated pleomorphic sarcoma (UPS) is defined as a sarcoma with cellular pleomorphism and no identifiable line of differentiation. It is typically a high-grade lesion with a metastatic rate of about one third. No tumor-specific rearrangement has been identified, and genetic markers that could be used for treatment stratification are lacking. We performed transcriptome sequencing (RNA-Seq) to search for novel gene fusions. EXPERIMENTAL DESIGN: RNA-Seq, FISH, and/or various PCR methodologies were used to search for gene fusions and rearrangements of the PRDM10 gene in 84 soft tissue sarcomas. RESULTS: Using RNA-Seq, two cases of UPS were found to display novel gene fusions, both involving the transcription factor PRDM10 as the 3' partner and either MED12 or CITED2 as the 5' partner gene. Further screening of 82 soft tissue sarcomas for rearrangements of the PRDM10 locus revealed one more UPS with a MED12/PRDM10 fusion. None of these genes has been implicated in neoplasia-associated gene fusions before. CONCLUSIONS: Our results suggest that PRDM10 fusions are present in around 5% of UPS. Although the fusion-positive cases in our series showed the same nuclear pleomorphism and lack of differentiation as other UPS, it is noteworthy that all three were morphologically low grade and that none of the patients developed metastases. Thus, PRDM10 fusion-positive sarcomas may constitute a clinically important subset of UPS.


Assuntos
Proteínas de Ligação a DNA/genética , Fusão Gênica/genética , Sarcoma/genética , Neoplasias de Tecidos Moles/genética , Fatores de Transcrição/genética , Cariótipo Anormal , Humanos , Hibridização in Situ Fluorescente , Complexo Mediador/genética , Reação em Cadeia da Polimerase em Tempo Real , Proteínas Repressoras/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transativadores/genética
9.
Am J Surg Pathol ; 38(6): 801-8, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24441665

RESUMO

Sclerosing epithelioid fibrosarcoma (SEF) and low-grade fibromyxoid sarcoma (LGFMS) are 2 distinct types of sarcoma, with a subset of cases showing overlapping morphologic and immunohistochemical features. LGFMS is characterized by expression of the MUC4 protein, and about 90% of cases display a distinctive FUS-CREB3L2 gene fusion. In addition, SEF is often MUC4 positive, but is genetically less well studied. Fluorescence in situ hybridization (FISH) studies have shown involvement of the FUS gene in the majority of so-called hybrid LGFMS/SEF and in 10% to 25% of sarcomas with pure SEF morphology. In this study, we investigated a series of 10 primary tumors showing pure SEF morphology, 4 cases of LGFMS that at local or distant relapse showed predominant SEF morphology, and 1 primary hybrid LGFMS/SEF. All but 1 case showed diffuse expression for MUC4. Using FISH, reverse transcription polymerase chain reaction, and/or mRNA sequencing in selected cases, we found recurrent EWSR1-CREB3L1 fusion transcripts by reverse transcription polymerase chain reaction in 3/10 pure SEF cases and splits and deletions of the EWSR1 and/or CREB3L1 genes by FISH in 6 additional cases. All 5 cases of LGFMS with progression to SEF morphology or hybrid features had FUS-CREB3L2 fusion transcripts. Our results indicate that EWSR1 and CREB3L1 rearrangements are predominant over FUS and CREB3L2 rearrangements in pure SEF, highlighting that SEF and LGFMS are different tumor types, with different impacts on patient outcome.


Assuntos
Biomarcadores Tumorais/genética , Proteínas de Ligação a Calmodulina/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Células Epitelioides , Fibroma/genética , Fibrossarcoma/genética , Fusão Gênica , Proteínas do Tecido Nervoso/genética , Proteínas de Ligação a RNA/genética , Neoplasias de Tecidos Moles/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Células Epitelioides/química , Células Epitelioides/patologia , Feminino , Fibroma/química , Fibroma/patologia , Fibrossarcoma/química , Fibrossarcoma/secundário , Rearranjo Gênico , Predisposição Genética para Doença , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Mucina-4/análise , Gradação de Tumores , Recidiva Local de Neoplasia , Fenótipo , RNA Mensageiro/análise , Proteína EWS de Ligação a RNA , Proteína FUS de Ligação a RNA/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Esclerose , Análise de Sequência de RNA , Neoplasias de Tecidos Moles/química , Neoplasias de Tecidos Moles/patologia , Adulto Jovem
10.
Int J Biochem Cell Biol ; 53: 475-81, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24721208

RESUMO

Benign fibrous histiocytoma (BFH) is a mesenchymal tumor that most often occurs in the skin (so-called dermatofibroma), but may also appear in soft tissues (so-called deep BFH) and in the skeleton (so-called non-ossifying fibroma). The origin of BFH is unknown, and it has been questioned whether it is a true neoplasm. Chromosome banding, fluorescence in situ hybridization, single nucleotide polymorphism arrays, RNA sequencing, RT-PCR and quantitative real-time PCR were used to search for recurrent somatic mutations in a series of BFH. BFHs were found to harbor recurrent fusions of genes encoding membrane-associated proteins (podoplanin, CD63 and LAMTOR1) with genes encoding protein kinase C (PKC) isoforms PRKCB and PRKCD. PKCs are serine-threonine kinases that through their many phosphorylation targets are implicated in a variety of cellular processes, as well as tumor development. When inactive, the amino-terminal, regulatory domain of PKCs suppresses the activity of their catalytic domain. Upon activation, which requires several steps, they typically translocate to cell membranes, where they interact with different signaling pathways. The detected PDPN-PRKCB, CD63-PRKCD and LAMTOR1-PRKCD gene fusions are all predicted to result in chimeric proteins consisting of the membrane-binding part of PDPN, CD63 or LAMTOR1 and the entire catalytic domain of the PKC. This novel pathogenetic mechanism should result in constitutive kinase activity at an ectopic location. The results show that BFH indeed is a true neoplasm, and that distorted PKC activity is essential for tumorigenesis. The findings also provide means to differentiate BFH from other skin and soft tissue tumors. This article is part of a Directed Issue entitled: Rare cancers.


Assuntos
Histiocitoma Fibroso Benigno/genética , Proteínas de Membrana/genética , Proteínas de Fusão Oncogênica/genética , Proteína Quinase C beta/genética , Proteína Quinase C-delta/genética , Adulto , Proteínas de Transporte/genética , Proteínas de Transporte/isolamento & purificação , Bandeamento Cromossômico , Endossomos/genética , Endossomos/patologia , Feminino , Histiocitoma Fibroso Benigno/patologia , Humanos , Hibridização in Situ Fluorescente , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/isolamento & purificação , Proteínas de Membrana/isolamento & purificação , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/isolamento & purificação , Polimorfismo de Nucleotídeo Único , Proteína Quinase C beta/isolamento & purificação , Proteína Quinase C-delta/isolamento & purificação , Transdução de Sinais , Tetraspanina 30/genética , Tetraspanina 30/isolamento & purificação
11.
Nat Genet ; 46(5): 474-7, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24658000

RESUMO

Glutamate receptors are well-known actors in the central and peripheral nervous systems, and altered glutamate signaling is implicated in several neurological and psychiatric disorders. It is increasingly recognized that such receptors may also have a role in tumor growth. Here we provide direct evidence of aberrant glutamate signaling in the development of a locally aggressive bone tumor, chondromyxoid fibroma (CMF). We subjected a series of CMFs to whole-genome mate-pair sequencing and RNA sequencing and found that the glutamate receptor gene GRM1 recombines with several partner genes through promoter swapping and gene fusion events. The GRM1 coding region remains intact, and 18 of 20 CMFs (90%) showed a more than 100-fold and up to 1,400-fold increase in GRM1 expression levels compared to control tissues. Our findings unequivocally demonstrate that direct targeting of GRM1 is a necessary and highly specific driver event for CMF development.


Assuntos
Neoplasias Ósseas/genética , Fibroma/genética , Regulação Neoplásica da Expressão Gênica/genética , Receptores de Glutamato Metabotrópico/genética , Transdução de Sinais/genética , Sequência de Bases , Bandeamento Cromossômico , Variações do Número de Cópias de DNA , Fusão Gênica/genética , Humanos , Hibridização in Situ Fluorescente , Dados de Sequência Molecular , Países Baixos , Regiões Promotoras Genéticas/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptores de Glutamato Metabotrópico/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sequência de RNA
12.
Genes (Basel) ; 3(3): 361-77, 2012 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-24704974

RESUMO

The bacterium Xanthomonas campestris pathovar musacearum (Xcm) is the causal agent of banana Xanthomonas wilt (BXW). This disease has devastated economies based on banana and plantain crops (Musa species) in East Africa. Here we use genome-wide sequencing to discover a set of single-nucleotide polymorphisms (SNPs) among East African isolates of Xcm. These SNPs have potential as molecular markers for phylogeographic studies of the epidemiology and spread of the pathogen. Our analysis reveals two major sub-lineages of the pathogen, suggesting that the current outbreaks of BXW on Musa species in the region may have more than one introductory event, perhaps from Ethiopia. Also, based on comparisons of genome-wide sequence data from multiple isolates of Xcm and multiple strains of X. vasicola pathovar vasculorum, we identify genes specific to Xcm that could be used to specifically detect Xcm by PCR-based methods.

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