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

被引:17
作者
Antic, Zeljko [1 ]
Yu, Jiangyan [1 ,2 ]
van Reijmersdal, Simon, V [1 ,3 ]
van Dijk, Anke [2 ]
Dekker, Linde [1 ]
Segerink, Wouter H. [1 ]
Sonneveld, Edwin [1 ,3 ]
Fiocco, Marta [1 ,4 ,5 ]
Pieters, Rob [1 ,3 ]
Hoogerbrugge, Peter M. [1 ,3 ]
Van Leeuwen, Frank N. [1 ]
Van Kessel, Ad Geurts [2 ]
Waanders, Esme [1 ,6 ]
Kuiper, Roland P. [1 ,6 ]
机构
[1] Princess Maxima Ctr Pediat Oncol, Utrecht, Netherlands
[2] Radboud Univ Nijmegen, Med Ctr, Radboud Inst Mol Life Sci, Dept Human Genet, Nijmegen, Netherlands
[3] Dutch Childhood Oncol Grp, Utrecht, Netherlands
[4] Leiden Univ, Med Ctr, Dept Biomed Data Sci, Med Stat, Leiden, Netherlands
[5] Leiden Univ, Math Inst, Leiden, Netherlands
[6] Univ Med Ctr Utrecht, Dept Genet, Utrecht, Netherlands
关键词
B-CELL PRECURSOR; IKZF1; DELETION; CREBBP MUTATIONS; RESISTANCE; RELAPSE; NT5C2; CHILDREN; MARKER; IMPACT; PULSES;
D O I
10.3324/haematol.2020.259226
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
引用
收藏
页码:3046 / 3055
页数:10
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