Characterization and diagnostic application of genomic fusion sequences in anaplastic large-cell lymphoma
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Characterization and diagnostic application of genomic 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.
in: ONCOTARGET, Jahrgang 9, Nr. 41, 29.05.2018, S. 26543-26555.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Characterization and diagnostic application of genomic 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 - 2018/5/29
Y1 - 2018/5/29
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 - Journal Article
U2 - 10.18632/oncotarget.25489
DO - 10.18632/oncotarget.25489
M3 - SCORING: Journal article
C2 - 29899875
VL - 9
SP - 26543
EP - 26555
JO - ONCOTARGET
JF - ONCOTARGET
SN - 1949-2553
IS - 41
ER -