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Transcriptome sequencing in pediatric acute lymphoblastic leukemia identifies fusion genes associated with distinct DNA methylation profiles
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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2017 (English)In: Journal of Hematology & Oncology, ISSN 1756-8722, E-ISSN 1756-8722, Vol. 10, article id 148Article in journal (Refereed) Published
Abstract [en]

Background: Structural chromosomal rearrangements that lead to expressed fusion genes are a hallmark of acute lymphoblastic leukemia (ALL). In this study, we performed transcriptome sequencing of 134 primary ALL patient samples to comprehensively detect fusion transcripts. Methods: We combined fusion gene detection with genome-wide DNA methylation analysis, gene expression profiling, and targeted sequencing to determine molecular signatures of emerging ALL subtypes. Results: We identified 64 unique fusion events distributed among 80 individual patients, of which over 50% have not previously been reported in ALL. Although the majority of the fusion genes were found only in a single patient, we identified several recurrent fusion gene families defined by promiscuous fusion gene partners, such as ETV6, RUNX1, PAX5, and ZNF384, or recurrent fusion genes, such as DUX4-IGH. Our data show that patients harboring these fusion genes displayed characteristic genome-wide DNA methylation and gene expression signatures in addition to distinct patterns in single nucleotide variants and recurrent copy number alterations. Conclusion: Our study delineates the fusion gene landscape in pediatric ALL, including both known and novel fusion genes, and highlights fusion gene families with shared molecular etiologies, which may provide additional information for prognosis and therapeutic options in the future.

Place, publisher, year, edition, pages
2017. Vol. 10, article id 148
Keyword [en]
Pediatric acute lymphoblastic leukemia, RNA sequencing, Fusion genes, BCP-ALL, T-ALL, Translocation
National Category
Cancer and Oncology Pediatrics
Identifiers
URN: urn:nbn:se:uu:diva-332658DOI: 10.1186/s13045-017-0515-yISI: 000408001300001PubMedID: 28806978OAI: oai:DiVA.org:uu-332658DiVA, id: diva2:1153725
Funder
Swedish Foundation for Strategic Research , RBc08-008Swedish Cancer Society, 130440, 160711Swedish Childhood Cancer Foundation, 11098Swedish Research Council, C0524801, 2016-03691_3
Note

De 2 sista författarna delar sistaförfattarskapet.

Available from: 2017-10-31 Created: 2017-10-31 Last updated: 2018-04-02Bibliographically approved
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
Keyword
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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Available from: 2018-05-02 Created: 2018-04-02 Last updated: 2018-05-02

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Marincevic-Zuniga, YanaraDahlberg, JohanNilsson, SaraRaine, AmandaNystedt, SaraLindqvist, Carl MårtenBerglund, Eva C.Cavelier, LuciaLönnerholm, GudmarNordlund, JessicaSyvänen, Ann-Christine
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