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

• Published in: Haematologica (Roma) Vol. 104; no. 7; pp. 1407 - 1416
• Main Authors: Zaliova, Marketa, Potuckova, Eliska, Hovorkova, Lenka, Musilova, Alena, Winkowska, Lucie, Fiser, Karel, Stuchly, Jan, Mejstrikova, Ester, Starkova, Julia, Zuna, Jan, Stary, Jan, Trka, Jan
• Format: Journal Article
• Language: English
• Published: Italy Ferrata Storti Foundation 01-07-2019
• ISSN: 0390-6078; 1592-8721
• DOI: 10.3324/haematol.2018.204487

-deletions occur recurrently in acute lymphoblastic leukemia, especially in the
-rearranged subtype. The
-deletion was shown to positively impact prognosis of patients with
-deletion and its presence precludes assignment into
group, a novel high-risk category on AIEOP-BFM ALL trials. We analyzed the impact of different methods on
-deletion detection rate, evaluated
-deletion as a potential marker for
-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
-deletion in 34% (16 of 47), 66% (33 of 50) and 78% (39 of 50) of
-rearranged leukemia, respectively. False negativity of
-deletion by single-nucleotide-polymorphism array caused
misclassification in 5 patients. No
-deletion was found outside the
-rearranged cases. Within
-rearranged leukemia, the
-deletion was associated with higher total number of copy-number aberrations, and, importantly, the
-deletion positivity by PCR was associated with better outcome [5-year event-free survival (EFS),
-deletion-positive 93%
-deletion-negative 68%,
=0.022; 5-year overall survival (OS),
-deletion-positive 97%
-deletion-negative 75%,
=0.029]. Ultra-deep amplicon-sequencing revealed distinct co-existing
-deletions in 22 of 24 patients. In conclusion, our data demonstrate inadequate sensitivity of single-nucleotide-polymorphism array for
-deletion detection, unacceptable for proper
classification. Even using more sensitive methods (PCR/amplicon-sequencing) for its detection,
-deletion is absent in 22-34% of
-rearranged leukemia and does not represent an adequately sensitive marker of this leukemia subtype. Importantly, the
-deletion potentially stratifies the
-rearranged leukemia into biologically/clinically distinct subsets. Frequent polyclonal pattern of
-deletions shows that late origin of this lesion is more common than has been previously described.