| Autor: |
Antić Ž; Princess Maxima Center for Pediatric Oncology, Utrecht., Yu J; Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands; Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen., Van Reijmersdal SV; Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands; Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen., Van Dijk A; Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen., Dekker L; Princess Maxima Center for Pediatric Oncology, Utrecht., Segerink WH; Princess Maxima Center for Pediatric Oncology, Utrecht., Sonneveld E; Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands; Dutch Childhood Oncology Group, Utrecht., Fiocco M; Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands; Medical Statistics, Department of Biomedical Data Science, Leiden University Medical Center, Leiden, The Netherlands; Mathematical Institute, Leiden University., Pieters R; Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands; Dutch Childhood Oncology Group, Utrecht., Hoogerbrugge PM; Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands; Dutch Childhood Oncology Group, Utrecht., Van Leeuwen FN; Princess Maxima Center for Pediatric Oncology, Utrecht., Van Kessel AG; Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen., Waanders E; Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands; Department of Genetics, University Medical Center Utrecht, Utrecht., Kuiper RP; Princess Maxima Center for Pediatric Oncology, Utrecht. r.kuiper@prinsesmaximacentrum.nl. |
| Abstrakt: |
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 PCR we reliably detected alterations below 1% allele frequency. We identified 660 genomic alterations in 285 diagnosis 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. |
