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

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*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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.

Original languageEnglish
Pages (from-to)3046-3055
Number of pages10
JournalHaematologica
Volume106
Issue number12
DOIs
Publication statusPublished - 1 Dec 2021

Keywords

  • Child
  • Clone Cells
  • Genomics
  • Humans
  • Mutation
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma/diagnosis
  • Prognosis

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