Open AccessERG deletions in childhood acute lymphoblastic leukemia with DUX4 rearrangements are mostly polyclonal, prognostically relevant and their detection rate strongly depends on screening method sensitivity
Author(s) -
Markéta Žaliová,
Eliška Potůčková,
Lenka Hovorková,
Alena Musilová,
Lucie Winkowska,
Karel Fišer,
Jan Stuchlý,
Ester Mejstříková,
Júlia Starková,
Jan Zuna,
Jan Starý,
Jan Trka
Publication year - 2019
Publication title -
haematologica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.782
H-Index - 142
eISSN - 1592-8721
pISSN - 0390-6078
DOI - 10.3324/haematol.2018.204487
Subject(s) - amplicon , erg , biology , microbiology and biotechnology , leukemia , genetics , polymerase chain reaction , gene , retina , neuroscience
ERG -deletions occur recurrently in acute lymphoblastic leukemia, especially 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 IKZF1 plus group, a novel high-risk category on AIEOP-BFM ALL trials. We analyzed the impact of different methods on ERG -deletion detection rate, evaluated ERG -deletion as a potential marker for DUX4 -rearranged leukemia, studied its associations with molecular and clinical characteristics within this leukemia subtype, and analyzed its clonality. Using single-nucleotide-polymorphism array, genomic polymerase chain reaction (PCR) and amplicon-sequencing we found ERG -deletion 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 single-nucleotide-polymorphism array caused IKZF1 plus 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 IKZF1 plus 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/clinically distinct subsets. Frequent polyclonal pattern of ERG -deletions shows that late origin of this lesion is more common than has been previously described.