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Multiclonal complexity of pediatric acute lymphoblastic leukemia and the prognostic relevance of subclonal mutations

Authors :
Željko Antić
Jiangyan Yu
Simon V. van Reijmersdal
Anke van Dijk
Linde Dekker
Wouter H. Segerink
Edwin Sonneveld
Marta Fiocco
Rob Pieters
Peter M. Hoogerbrugge
Frank N. van Leeuwen
Ad Geurts van Kessel
Esme Waanders
Roland P. Kuiper
Source :
Haematologica, Vol 106, Iss 12 (2020)
Publication Year :
2020
Publisher :
Ferrata Storti Foundation, 2020.

Abstract

Genomic studies of pediatric acute lymphoblastic leukemia (ALL) have shown remarkable heterogeneity in initial diagnosis, with multiple (sub)clones harboring lesions in relapse-associated genes. However, the clinical relevance of these subclonal alterations remains unclear. We assessed the clinical relevance and prognostic value of subclonal alterations in the relapse-associated genes IKZF1, CREBBP, KRAS, NRAS, PTPN11, TP53, NT5C2, and WHSC1 in 503 ALL cases. Using molecular inversion probe sequencing and breakpoint-spanning polymerase chain reaction analysis we reliably detected alterations with an allele frequency below 1%. We identified 660 genomic alterations in 285 diagnostic samples of which 495 (75%) were subclonal. RAS pathway mutations were common, particularly in minor subclones, and comparisons between RAS hotspot mutations revealed differences in their capacity to drive clonal expansion in ALL. We did not find an association of subclonal alterations with unfavorable outcome. Particularly for IKZF1, an established prognostic marker in ALL, all clonal but none of the subclonal alterations were preserved at relapse. We conclude that, for the genes tested, there is no basis to consider subclonal alterations detected at diagnosis for risk group stratification of ALL treatment.

Details

Language :
English
ISSN :
03906078 and 15928721
Volume :
106
Issue :
12
Database :
Directory of Open Access Journals
Journal :
Haematologica
Publication Type :
Academic Journal
Accession number :
edsdoj.9dc8ce692dab4b10b6bd519bb4040df0
Document Type :
article
Full Text :
https://doi.org/10.3324/haematol.2020.259226