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DNA methylation classification in combination with RNA-sequencing for subtype discovery in pediatric B-cell precursor acute lymphoblastic leukemia
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
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(English)Manuscript (preprint) (Other academic)
National Category
Medical Genetics
Research subject
Medical Genetics
Identifiers
URN: urn:nbn:se:uu:diva-344661OAI: oai:DiVA.org:uu-344661DiVA, id: diva2:1194067
Available from: 2018-03-28 Created: 2018-03-28 Last updated: 2018-04-02
In thesis
1. Resolving the Genomic Complexity of Pediatric Acute Lymphoblastic Leukemia
Open this publication in new window or tab >>Resolving the Genomic Complexity of Pediatric Acute Lymphoblastic Leukemia
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer in the Nordic countries. Structural chromosomal rearrangements are a hallmark of ALL and represent key markers for diagnosis, risk stratification and prognosis. Nevertheless, a substantial proportion of ALL cases (~25%) lack known risk-stratifying markers and are commonly referred to as the B-other subgroup. Improved delineation of structural alterations within this subgroup could provide additional information for diagnosis, prognosis and treatment decisions. Therefore, the aim of this thesis was to decipher the genetic alterations in pediatric ALL, focusing on patients in the B-other subgroup that lack known risk-stratifying markers, and to gain further understanding of the prognostic relevance of aberrant chromosomal changes in ALL.

This thesis comprises four studies. In study I we identified a novel and recurrent fusion gene (PAX5-ESRRB) in four B-other patients using a combination of RNA-sequencing and copy number analysis. These patients displayed a distinct gene expression and DNA-methylation pattern that differed from other subtypes of ALL. In study II we further explored the fusion gene landscape in ALL by applying RNA-sequencing to 134 patient samples assigned to different subtypes, including the B-other subgroup. We detected several novel and recurrent fusion gene families in approximately 80% of the B-other patients of which several were associated with distinct DNA methylation and gene expression profiles. Following on from study II, in study III we utilized subtype-specific DNA methylation patterns to design DNA methylation-based classifiers to screen for subtype membership in ~1100 ALL samples including a large group of B-other samples (25%). Re-classification of B-other samples into a new subtype using DNA methylation as the sole marker for subtype classification was validated by RNA-sequencing, which identified previously unknown fusion genes. In study IV, “linked-read” whole genome sequencing was applied to 13 ALL samples for in-depth analysis of chromosomal rearrangements. We detected all known pathogenic variants with this technique and also identified previously unknown structural aberrations at a resolution beyond that obtained by traditional karyotyping.

Together, these studies provide novel insights into the structural variation present in ALL and their potential clinical relevance, which may contribute to improved treatment stratification and risk-evaluation of children diagnosed with ALL in the future.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 47
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1452
Keywords
Acute lymphoblastic leukemia (ALL), 450k array, DNA methylation, RNA-sequencing, linked-read WGS, B-other, fusion gene, chromosomal translocation
National Category
Medical Genetics Cancer and Oncology Hematology
Research subject
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-345085 (URN)978-91-513-0302-4 (ISBN)
Public defence
2018-05-25, E10:1307-1309, Navet, SciLifeLab (BMC), Husargatan 3, Uppsala, 09:00 (English)
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Supervisors
Available from: 2018-05-02 Created: 2018-04-02 Last updated: 2018-05-02

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Marincevic-Zuniga, YanaraNystedt, SaraNilsson, SaraAlmlöf, Jonas CarlssonLönnerholm, GudmarNordlund, Jessica

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Marincevic-Zuniga, YanaraNystedt, SaraNilsson, SaraAlmlöf, Jonas CarlssonLönnerholm, GudmarNordlund, Jessica
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Molecular MedicineScience for Life Laboratory, SciLifeLabNeuropediatrics/Paediatric oncology
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