Characterization and diagnostic application of genomic NPMALK fusion sequences in anaplastic large-cell lymphoma

Manuela Krumbholz*, Wilhelm Woessmann, Jakob Zierk, David Seniuk, Paolo Ceppi, Martin Zimmermann, Vijay Kumar Singh, Markus Metzler, Christine Damm-Welk

*Kontaktforfatter for dette arbejde

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) fusion genes resulting from the translocation t(2;5)(p23;q35) are present in almost 90% of childhood ALK-positive anaplastic large-cell lymphomas (ALCL). Detection and quantification of minimal disseminated disease (MDD) by measuring NPM-ALK fusion transcript levels in the blood provide independent prognostic parameters. Characterization of the genomic breakpoints provides insights into the pathogenesis of the translocation and allows for DNA-based minimal disease monitoring. We designed a nested multiplex PCR assay for identification and characterization of genomic NPM-ALK fusion sequences in 45 pediatric ALCL-patients, and used the sequences for quantitative MDD monitoring. Breakpoint analysis indicates the involvement of inaccurate non-homologous end joining repair mechanisms in the formation of NPM-ALK fusions. Parallel quantification of RNA and DNA levels in the cellular fraction of 45 blood samples from eight patients with NPM-ALK-positive ALCL correlated, as did cell-free circulating NPM-ALK DNA copies in the plasma fraction of 37 blood samples. With genomic NPM-ALK fusion sequence quantification, plasma samples of ALCL patients become an additional source for MRD-assessment. Parallel quantification of NPM-ALK transcripts and fusion genes in ALCL cell lines treated with the ALK kinase inhibitor crizotinib illustrates the potential value of supplementary DNA-based quantification in particular clinical settings.

OriginalsprogEngelsk
TidsskriftOncotarget
Vol/bind9
Udgave nummer41
Sider (fra-til)26543-26555
Antal sider13
ISSN1949-2553
DOI
StatusUdgivet - 2018
Udgivet eksterntJa

Fingeraftryk

Anaplastic Large-Cell Lymphoma
DNA
nucleophosmin
Multiplex Polymerase Chain Reaction
RNA
Pediatrics
Cell Line
Polymerase Chain Reaction

Citer dette

Krumbholz, M., Woessmann, W., Zierk, J., Seniuk, D., Ceppi, P., Zimmermann, M., ... Damm-Welk, C. (2018). Characterization and diagnostic application of genomic NPMALK fusion sequences in anaplastic large-cell lymphoma. Oncotarget, 9(41), 26543-26555. https://doi.org/10.18632/oncotarget.25489
Krumbholz, Manuela ; Woessmann, Wilhelm ; Zierk, Jakob ; Seniuk, David ; Ceppi, Paolo ; Zimmermann, Martin ; Singh, Vijay Kumar ; Metzler, Markus ; Damm-Welk, Christine. / Characterization and diagnostic application of genomic NPMALK fusion sequences in anaplastic large-cell lymphoma. I: Oncotarget. 2018 ; Bind 9, Nr. 41. s. 26543-26555.
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title = "Characterization and diagnostic application of genomic NPMALK fusion sequences in anaplastic large-cell lymphoma",
abstract = "Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) fusion genes resulting from the translocation t(2;5)(p23;q35) are present in almost 90{\%} of childhood ALK-positive anaplastic large-cell lymphomas (ALCL). Detection and quantification of minimal disseminated disease (MDD) by measuring NPM-ALK fusion transcript levels in the blood provide independent prognostic parameters. Characterization of the genomic breakpoints provides insights into the pathogenesis of the translocation and allows for DNA-based minimal disease monitoring. We designed a nested multiplex PCR assay for identification and characterization of genomic NPM-ALK fusion sequences in 45 pediatric ALCL-patients, and used the sequences for quantitative MDD monitoring. Breakpoint analysis indicates the involvement of inaccurate non-homologous end joining repair mechanisms in the formation of NPM-ALK fusions. Parallel quantification of RNA and DNA levels in the cellular fraction of 45 blood samples from eight patients with NPM-ALK-positive ALCL correlated, as did cell-free circulating NPM-ALK DNA copies in the plasma fraction of 37 blood samples. With genomic NPM-ALK fusion sequence quantification, plasma samples of ALCL patients become an additional source for MRD-assessment. Parallel quantification of NPM-ALK transcripts and fusion genes in ALCL cell lines treated with the ALK kinase inhibitor crizotinib illustrates the potential value of supplementary DNA-based quantification in particular clinical settings.",
keywords = "ALK-positive anaplastic large cell lymphoma, Genomic fusion sequences, Minimal disease monitoring, NPM-ALK fusion, Pediatric oncology",
author = "Manuela Krumbholz and Wilhelm Woessmann and Jakob Zierk and David Seniuk and Paolo Ceppi and Martin Zimmermann and Singh, {Vijay Kumar} and Markus Metzler and Christine Damm-Welk",
year = "2018",
doi = "10.18632/oncotarget.25489",
language = "English",
volume = "9",
pages = "26543--26555",
journal = "OncoTarget",
issn = "1949-2553",
publisher = "Impact Journals LLC",
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Krumbholz, M, Woessmann, W, Zierk, J, Seniuk, D, Ceppi, P, Zimmermann, M, Singh, VK, Metzler, M & Damm-Welk, C 2018, 'Characterization and diagnostic application of genomic NPMALK fusion sequences in anaplastic large-cell lymphoma', Oncotarget, bind 9, nr. 41, s. 26543-26555. https://doi.org/10.18632/oncotarget.25489

Characterization and diagnostic application of genomic NPMALK fusion sequences in anaplastic large-cell lymphoma. / Krumbholz, Manuela; Woessmann, Wilhelm; Zierk, Jakob; Seniuk, David; Ceppi, Paolo; Zimmermann, Martin; Singh, Vijay Kumar; Metzler, Markus; Damm-Welk, Christine.

I: Oncotarget, Bind 9, Nr. 41, 2018, s. 26543-26555.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Characterization and diagnostic application of genomic NPMALK fusion sequences in anaplastic large-cell lymphoma

AU - Krumbholz, Manuela

AU - Woessmann, Wilhelm

AU - Zierk, Jakob

AU - Seniuk, David

AU - Ceppi, Paolo

AU - Zimmermann, Martin

AU - Singh, Vijay Kumar

AU - Metzler, Markus

AU - Damm-Welk, Christine

PY - 2018

Y1 - 2018

N2 - Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) fusion genes resulting from the translocation t(2;5)(p23;q35) are present in almost 90% of childhood ALK-positive anaplastic large-cell lymphomas (ALCL). Detection and quantification of minimal disseminated disease (MDD) by measuring NPM-ALK fusion transcript levels in the blood provide independent prognostic parameters. Characterization of the genomic breakpoints provides insights into the pathogenesis of the translocation and allows for DNA-based minimal disease monitoring. We designed a nested multiplex PCR assay for identification and characterization of genomic NPM-ALK fusion sequences in 45 pediatric ALCL-patients, and used the sequences for quantitative MDD monitoring. Breakpoint analysis indicates the involvement of inaccurate non-homologous end joining repair mechanisms in the formation of NPM-ALK fusions. Parallel quantification of RNA and DNA levels in the cellular fraction of 45 blood samples from eight patients with NPM-ALK-positive ALCL correlated, as did cell-free circulating NPM-ALK DNA copies in the plasma fraction of 37 blood samples. With genomic NPM-ALK fusion sequence quantification, plasma samples of ALCL patients become an additional source for MRD-assessment. Parallel quantification of NPM-ALK transcripts and fusion genes in ALCL cell lines treated with the ALK kinase inhibitor crizotinib illustrates the potential value of supplementary DNA-based quantification in particular clinical settings.

AB - Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) fusion genes resulting from the translocation t(2;5)(p23;q35) are present in almost 90% of childhood ALK-positive anaplastic large-cell lymphomas (ALCL). Detection and quantification of minimal disseminated disease (MDD) by measuring NPM-ALK fusion transcript levels in the blood provide independent prognostic parameters. Characterization of the genomic breakpoints provides insights into the pathogenesis of the translocation and allows for DNA-based minimal disease monitoring. We designed a nested multiplex PCR assay for identification and characterization of genomic NPM-ALK fusion sequences in 45 pediatric ALCL-patients, and used the sequences for quantitative MDD monitoring. Breakpoint analysis indicates the involvement of inaccurate non-homologous end joining repair mechanisms in the formation of NPM-ALK fusions. Parallel quantification of RNA and DNA levels in the cellular fraction of 45 blood samples from eight patients with NPM-ALK-positive ALCL correlated, as did cell-free circulating NPM-ALK DNA copies in the plasma fraction of 37 blood samples. With genomic NPM-ALK fusion sequence quantification, plasma samples of ALCL patients become an additional source for MRD-assessment. Parallel quantification of NPM-ALK transcripts and fusion genes in ALCL cell lines treated with the ALK kinase inhibitor crizotinib illustrates the potential value of supplementary DNA-based quantification in particular clinical settings.

KW - ALK-positive anaplastic large cell lymphoma

KW - Genomic fusion sequences

KW - Minimal disease monitoring

KW - NPM-ALK fusion

KW - Pediatric oncology

U2 - 10.18632/oncotarget.25489

DO - 10.18632/oncotarget.25489

M3 - Journal article

C2 - 29899875

AN - SCOPUS:85047639604

VL - 9

SP - 26543

EP - 26555

JO - OncoTarget

JF - OncoTarget

SN - 1949-2553

IS - 41

ER -