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Acute Lymphoblastic Leukemia
ERG deletions in childhood acute lymphoblastic leukemia with DUX4 rearrangements are mostly polyclonal, prognostically relevant and their detection rate strongly depends on screening method sensitivity
Ferrata Storti Foundation
Haematologica 2019 Volume 104(7):1407-1416
Marketa Zaliova,1,2,3 Eliska Potuckova,1,2 Lenka Hovorkova,1,2 Alena Musilova,1,2 Lucie Winkowska,1,2 Karel Fiser,1,2 Jan Stuchly,1,2 Ester Mejstrikova,1,2,3 Julia Starkova,1,2 Jan Zuna,1,2,3 Jan Stary2,3 and Jan Trka1,2,3
1CLIP - Childhood Leukaemia Investigation Prague; 2Department of Paediatric Haematology and Oncology, Second Faculty of Medicine, Charles University, Prague and 3University Hospital Motol, Prague, Czech Republic
ABSTRACT
ERG-deletions occur recurrently in acute lymphoblastic leukemia, espe- cially in the DUX4-rearranged subtype. The ERG-deletion was shown to positively impact prognosis of patients with IKZF1-deletion and its presence precludes assignment into IKZF1plus group, a novel high-risk cate- gory on AIEOP-BFM ALL trials. We analyzed the impact of different meth- ods on ERG-deletion detection rate, evaluated ERG-deletion as a potential marker for DUX4-rearranged leukemia, studied its associations with molec- ular and clinical characteristics within this leukemia subtype, and analyzed its clonality. Using single-nucleotide-polymorphism array, genomic poly- merase chain reaction (PCR) and amplicon-sequencing we found ERG-dele- tion in 34% (16 of 47), 66% (33 of 50) and 78% (39 of 50) of DUX4- rearranged leukemia, respectively. False negativity of ERG-deletion by sin- gle-nucleotide-polymorphism array caused IKZF1plus misclassification in 5 patients. No ERG-deletion was found outside the DUX4-rearranged cases. Within DUX4-rearranged leukemia, the ERG-deletion was associated with higher total number of copy-number aberrations, and, importantly, the ERG-deletion positivity by PCR was associated with better outcome [5- year event-free survival (EFS), ERG-deletion-positive 93% vs. ERG-deletion- negative 68%, P=0.022; 5-year overall survival (OS), ERG-deletion-positive 97% vs. ERG-deletion-negative 75%, P=0.029]. Ultra-deep amplicon- sequencing revealed distinct co-existing ERG-deletions in 22 of 24 patients. In conclusion, our data demonstrate inadequate sensitivity of single- nucleotide-polymorphism array for ERG-deletion detection, unacceptable for proper IKZF1plus classification. Even using more sensitive methods (PCR/amplicon-sequencing) for its detection, ERG-deletion is absent in 22- 34% of DUX4-rearranged leukemia and does not represent an adequately sensitive marker of this leukemia subtype. Importantly, the ERG-deletion potentially stratifies the DUX4-rearranged leukemia into biologically/clini- cally distinct subsets. Frequent polyclonal pattern of ERG-deletions shows that late origin of this lesion is more common than has been previously described.
Introduction
ERG (ETS transcription factor) gene deletions (ERGdel) can be found in 3-7% of pediatric B-cell precursor (BCP) acute lymphoblastic leukemia (ALL).1-3 It occurs almost exclusively in B-other ALL, a heterogeneous subset comprising 20-25% of pediatric BCP-ALL, defined by the absence of routinely tested (cyto)genetic classi-
Correspondence:
MARKETA ZALIOVA
marketa.zaliova@lfmotol.cuni.cz
Received: August 13, 2018. Accepted: January 7, 2019. Pre-published: January 10, 2019.
doi:10.3324/haematol.2018.204487
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/7/1407
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haematologica | 2019; 104(7)
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