Journal
HEMASPHERE
Volume 6, Issue 10, Pages -Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/HS9.0000000000000785
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Funding
- Swedish Childhood Cancer Fund
- Swedish Cancer Society
- Swedish Research Council
- Knut and Alice Wallenberg Foundation
- Crafoord Foundation
- Per-Eric and Ulla Schyberg Foundation
- Nilsson-Ehle Donations
- Governmental Funding of Clinical Research within the National Health Service
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Infants and children with KMT2A-gene rearrangements in acute lymphoblastic leukemia (ALL) often carry low-frequency cancer-associated mutations, indicating a wide subclonal genetic landscape.
Infant acute lymphoblastic leukemia (ALL) with KMT2A-gene rearrangements (KMT2A-r) have few mutations and a poor prognosis. To uncover mutations that are below the detection of standard next-generation sequencing (NGS), a combination of targeted duplex sequencing and NGS was applied on 20 infants and 7 children with KMT2A-r ALL, 5 longitudinal and 6 paired relapse samples. Of identified nonsynonymous mutations, 87 had been previously implicated in cancer and targeted genes recurrently altered in KMT2A-r leukemia and included mutations in KRAS, NRAS, FLT3, TP53, PIK3CA, PAX5, PIK3R1, and PTPN11, with infants having fewer such mutations. Of identified cancer-associated mutations, 62% were below the resolution of standard NGS. Only 33 of 87 mutations exceeded 2% of cellular prevalence and most-targeted PI3K/RAS genes (31/33) and typically KRAS/NRAS. Five patients only had low-frequency PI3K/RAS mutations without a higher-frequency signaling mutation. Further, drug-resistant clones with FLT3(D835H) or NRAS(G13D/G12S) mutations that comprised only 0.06% to 0.34% of diagnostic cells, expanded at relapse. Finally, in longitudinal samples, the relapse clone persisted as a minor subclone from diagnosis and through treatment before expanding during the last month of disease. Together, we demonstrate that infant and childhood KMT2A-r ALL harbor low-frequency cancer-associated mutations, implying a vast subclonal genetic landscape.
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