Genetic and epigenetic characterization of hypodiploid acute lymphoblastic leukemia
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Setareh Safavi1, Linda Olsson1,2, Andrea Biloglav1, Srinivas Veerla3, Molly Blendberg1, Johnbosco Tayebwa1, Mikael Behrendtz4, Anders Castor5, Markus Hansson6, Bertil Johansson1,2, Kajsa Paulsson1
1Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden
2Department of Clinical Genetics, University and Regional Laboratories, Region Skåne, Lund, Sweden
3Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
4Department of Pediatrics, Linköping University Hospital, Linköping, Sweden
5Department of Pediatrics, Skåne University Hospital, Lund University, Lund, Sweden
6Division of Hematology, Skåne University Hospital, Lund University, Lund, Sweden
Setareh Safavi, e-mail: [email protected]
Kajsa Paulsson, e-mail: [email protected]
Keywords: acute lymphoblastic leukemia, hypodiploidy, next generation sequencing, chromosomal instability
Received: August 26, 2015 Accepted: October 17, 2015 Published: October 30, 2015
Purpose: To investigate the genetic and epigenetic landscape of hypodiploid (<45 chromosomes) acute lymphoblastic leukemia (ALL).
Methods: Single nucleotide polymorphism array, whole exome sequencing, RNA sequencing, and methylation array analyses were performed on eleven hypodiploid ALL cases.
Results: In line with previous studies, mutations in IKZF3 and FLT3 were detected in near-haploid (25–30 chromosomes) cases. Low hypodiploidy (31–39 chromosomes) was associated with somatic TP53 mutations. Notably, mutations of this gene were also found in 3/3 high hypodiploid (40–44 chromosomes) cases, suggesting that the mutational patterns are similar in low hypodiploid and high hypodiploid ALL. The high hypodiploid ALLs frequently displayed substantial cell-to-cell variability in chromosomal content, indicative of chromosomal instability; a rare phenomenon in ALL. Gene expression analysis showed that genes on heterodisomic chromosomes were more highly expressed in hypodiploid cases. Cases clustered according to hypodiploid subtype in the unsupervised methylation analyses, but there was no association between chromosomal copy number and methylation levels. A comparison between samples obtained at diagnosis and relapse showed that the relapse did not arise from the major diagnostic clone in 3/4 cases.
Conclusion: Taken together, our data support the conclusion that near-haploid and low hypodiploid ALL are different with regard to mutational profiles and also suggest that ALL cases with high hypodiploidy may harbor chromosomal instability.
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