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Ž. Antić et al.
have similar prognostic relevance as exon 4-7 deletions,31 suggesting that subclonal alterations in these other IKZF1 deletions may show the same lack of association.
In summary, we show that subclonal alterations in the relapse-associated genes IKZF1, CREBBP, KRAS, NRAS, PTPN11, TP53, and WHSC1 in pediatric ALL are fre- quently present at initial diagnosis, often at a subclonal level. At relapse, however, most of these subclonal muta- tions are lost, suggesting that their selective advantages over wild-type clones during treatment is limited. This finding has direct implications for clinical practice, par- ticularly in the case of IKZF1, where deletion status is used for routine risk stratification. We conclude that, at least for the investigated set of genes, there is no basis for the use of subclonal alterations at initial diagnosis as a prognostic marker.
Contributions
RPK, EW, FvL, and AGvK conceived the study. RPK, EW, ŽA and JY designed the study. PMH and RP are responsible for the clinical outcome data of patients included in the study. ŽA, JY, SVvR, AvD, LD and WHS performed experiments and analyzed the data. ŽA and MF performed statistical analyses. ŽA, JY and RPK wrote the manuscript and created the figures and tables. ES provided samples and clinical information. All authors critically reviewed the manuscript and approved the final submitted manuscript.
Acknowledgments
We thank Radboud University Medical Center, Department of Human Genetics for bioinformatic support in data analysis.
Funding
This work was supported by grants from Stichting Kinderen Kankervrij (KIKA 150 to RPK), Stichting Bergh in het Zadel (to RPK), and the China Scholarship Council (CSC201304910347 to JY).
Disclosures
No conflicts of interest to disclose.
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