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Ferrata Storti Foundation
Haematologica 2021 Volume 106(12):3046-3055
Multiclonal complexity of pediatric acute lymphoblastic leukemia and the prognostic relevance of subclonal mutations
Željko Antić,1* Jiangyan Yu,1,2* Simon V. van Reijmersdal,1,2 Anke van Dijk,2 Linde Dekker,1 Wouter H. Segerink,1 Edwin Sonneveld,1,3 Marta Fiocco,1,4,5 Rob Pieters,1,3 Peter M. Hoogerbrugge,1,3 Frank N. van Leeuwen,1
Ad Geurts van Kessel,2 Esmé Waanders1,6 and Roland P. Kuiper1,6
1Princess Máxima Center for Pediatric Oncology, Utrecht; 2Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen; 3Dutch Childhood Oncology Group, Utrecht; 4Medical Statistics, Department of Biomedical Data Science, Leiden University Medical Center, Leiden; 5Mathematical Institute, Leiden University and 6Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands
*ŽA and JY contributed equally as co-first authors.
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 path- way mutations were common, particularly in minor subclones, and com- parisons 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.
Introduction
Improvements in the treatment of pediatric acute lymphoblastic leukemia (ALL) have resulted in high overall survival rates, now approaching 90%.1,2 Nevertheless, relapse still remains the most common cause of treatment failure and death in chil- dren with ALL, and better recognition of individuals at risk of developing relapse will likely aid further improvements in outcome. Recent studies describing the genomic landscape of relapsed ALL have shown that relapse often originates from a minor (sub)clone at diagnosis, at a cellular fraction often undetectable by routine diagnostic methods.3-5 These minor (sub)clones harbor genomic alterations acquired later during leukemia development, which could potentially contribute to clonal drift, but are unlikely to be essential for initiation of the primary disease. However, selective pressure of the upfront treatment may provide a competitive advantage to subclones that harbor alterations in cancer genes, enabling their selec- tive survival, eventually leading to treatment failure. Both the number and clonal burden of the alterations in these genes are expected to be increased at the time of relapse, compared to initial diagnosis. Indeed, mutations in relapse-associated genes, such as those in the histone acetyltransferase (HAT) domain of the histone methyltransferase CREBBP, can often be traced back to minor subclones in the diagnostic sample.4,6,7
Acute Lymphoblastic Leukemia
Correspondence:
ROLAND P. KUIPER
r.kuiper@prinsesmaximacentrum.nl
Received: May 13, 2020. Accepted: October 23, 2020. Pre-published: November 5, 2020.
https://doi.org/10.3324/haematol.2020.259226 ©2021 Ferrata Storti Foundation
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