Molecular Genetic Characterization of Acute Lymphoblastic Leukemia with a Poor Prognosis
Author
Summary, in English
The general aim of my PhD project has been to characterize ALL patients with a poor prognosis, including adult ALL (article I) and hypodiploid ALL (article II-IV). To investigate the genetic landscape of adult ALL, we performed SNP array analysis on 126 ALL cases. Characteristic deletions seen in pediatric ALL were detected, furthermore, comparison of diagnostic and relapse clonal relationship showed evolution from an ancestral clone in the majority of cases, highlighting similarities in childhood and adult disease. In addition, the analysis revealed several recurrent cryptic genetic events not previously implicated with adult ALL, including the BCAT1, BTLA,
NR3C1, PIK3AP1 and SERP2 genes. In articles II-IV the genetic and epigenetic background of hypodiploid ALL was further investigated using SNP array analysis, exome and RNA sequencing, methylation array analysis and FISH analysis. Characteristic chromosomal patterns were confirmed and subtype specific alterations targeting IKZF3, NF1, FLT3 and TP53 were identified near-haploid and low hypodiploid respectively. Furthermore, due to the specific pattern of CDKN2A deletions in one case, we could conclude that chromosomal loss was the primary event with further microdeletions occurring after the near-haploidization. Combining SNP array and FISH analysis, a sublconal pattern was detected in three cases harboring >79 chromosomes, showing a possible hypodiploid origin due to the extensive loss of heterozygosity identified in such cases. That all three cases harbored TP53 mutations emphasized similarities to low hypodiploid ALL. In conclusion, screening for specific genetic abnormalities routinely in the clinic may improve prognostication and treatment stratification in cases with a poor prognosis.
Department/s
- Division of Clinical Genetics
- BioCARE: Biomarkers in Cancer Medicine improving Health Care, Education and Innovation
Publishing year
2015
Language
English
Publication/Series
Lund University Faculty of Medicine Doctoral Dissertation Series
Volume
2015:94
Full text
Document type
Dissertation
Publisher
Division of Clinical Genetics, Lund University
Topic
- Clinical Laboratory Medicine
Keywords
- Acute lymphoblastic leukemia
- hypodiploidy
- adult acute lymphoblastic leukemia
Status
Published
Supervisor
ISBN/ISSN/Other
- ISSN: 1652-8220
- ISBN: 978-91-7619-173-6
Defence date
16 October 2015
Defence time
13:00
Defence place
Belfragesalen BMC D15, Klinikgatan 32, Lund.
Opponent
- Julie Irving (Dr)