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Clonal and microclonal mutational heterogeneity in high hyperdiploid acute lymphoblastic leukemia.
- Source :
-
Oncotarget [Oncotarget] 2016 Nov 08; Vol. 7 (45), pp. 72733-72745. - Publication Year :
- 2016
-
Abstract
- High hyperdiploidy (HD), the most common cytogenetic subtype of B-cell acute lymphoblastic leukemia (B-ALL), is largely curable but significant treatment-related morbidity warrants investigating the biology and identifying novel drug targets. Targeted deep-sequencing of 538 cancer-relevant genes was performed in 57 HD-ALL patients lacking overt KRAS and NRAS hotspot mutations and lacking common B-ALL deletions to enrich for discovery of novel driver genes. One-third of patients harbored damaging mutations in epigenetic regulatory genes, including the putative novel driver DOT1L (n=4). Receptor tyrosine kinase (RTK)/Ras/MAPK signaling pathway mutations were found in two-thirds of patients, including novel mutations in ROS1, which mediates phosphorylation of the PTPN11-encoded protein SHP2. Mutations in FLT3 significantly co-occurred with DOT1L (p=0.04), suggesting functional cooperation in leukemogenesis. We detected an extraordinary level of tumor heterogeneity, with microclonal (mutant allele fraction <0.10) KRAS, NRAS, FLT3, and/or PTPN11 hotspot mutations evident in 31/57 (54.4%) patients. Multiple KRAS and NRAS codon 12 and 13 microclonal mutations significantly co-occurred within tumor samples (p=4.8x10-4), suggesting ongoing formation of and selection for Ras-activating mutations. Future work is required to investigate whether tumor microheterogeneity impacts clinical outcome and to elucidate the functional consequences of epigenetic dysregulation in HD-ALL, potentially leading to novel therapeutic approaches.
- Subjects :
- Epigenesis, Genetic
Gene Expression Regulation, Neoplastic
Genetic Predisposition to Disease
High-Throughput Nucleotide Sequencing
Humans
MAP Kinase Signaling System
Oncogenes
Precursor Cell Lymphoblastic Leukemia-Lymphoma metabolism
Signal Transduction
ras Proteins genetics
ras Proteins metabolism
Clonal Evolution genetics
Genetic Heterogeneity
Mutation
Polyploidy
Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1949-2553
- Volume :
- 7
- Issue :
- 45
- Database :
- MEDLINE
- Journal :
- Oncotarget
- Publication Type :
- Academic Journal
- Accession number :
- 27683039
- Full Text :
- https://doi.org/10.18632/oncotarget.12238