TY - JOUR
T1 - Multiclonal complexity of pediatric acute lymphoblastic leukemia and the prognostic relevance of subclonal mutations
AU - Antić, Željko
AU - Yu, Jiangyan
AU - Van Reijmersdal, Simon V
AU - Van Dijk, Anke
AU - Dekker, Linde
AU - Segerink, Wouter H
AU - Sonneveld, Edwin
AU - Fiocco, Marta
AU - Pieters, Rob
AU - Hoogerbrugge, Peter M
AU - Van Leeuwen, Frank N
AU - Van Kessel, Ad Geurts
AU - Waanders, Esme
AU - Kuiper, Roland P
N1 - Publisher Copyright:
© 2021 Ferrata Storti Foundation. All rights reserved.
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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.
AB - 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.
KW - Child
KW - Clone Cells
KW - Genomics
KW - Humans
KW - Mutation
KW - Precursor Cell Lymphoblastic Leukemia-Lymphoma/diagnosis
KW - Prognosis
UR - http://www.scopus.com/inward/record.url?scp=85095676161&partnerID=8YFLogxK
U2 - 10.3324/haematol.2020.259226
DO - 10.3324/haematol.2020.259226
M3 - Article
C2 - 33147938
SN - 0390-6078
VL - 106
SP - 3046
EP - 3055
JO - Haematologica
JF - Haematologica
IS - 12
ER -