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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
Keywords [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: 2018-08-27Bibliographically 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
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)
Opponent
Supervisors
Available from: 2018-05-02 Created: 2018-04-02 Last updated: 2018-10-08
2. Genetic Cartography at Massively Parallel Scale
Open this publication in new window or tab >>Genetic Cartography at Massively Parallel Scale
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Massively parallel sequencing (MPS) is revolutionizing genomics. In this work we use, refine, and develop new tools for the discipline.

MPS has led to the discovery of multiple novel subtypes in Acute Lymphoblastic Leukemia (ALL). In Study I we screen for fusion genes in 134 pediatric ALL patients, including patients without an assigned subtype. In approximately 80% of these patients we detect novel or known fusion gene families, most of which display distinct methylation and expression patterns. This shows the potential for improvements in the clinical stratification of ALL. Large sample sizes are important to detect recurrent somatic variation. In Study II we investigate if a non-index overlapping pooling schema can be used to increase sample size and detect somatic variation. We designed a schema for 172 ALL samples and show that it is possible to use this method to call somatic variants.

Around the globe there are many ongoing and completed genome projects. In Study III we sequenced the genome of 1000 Swedes to create a reference data set for the Swedish population. We identified more than 10 million variants that were not present in publicly available databases, highlighting the need for population-specific resources. Data, and the tools developed during this study, have been made publicly available as a resource for genomics in Sweden and abroad.

The increased amount of sequencing data has created a greater need for automation. In Study IV we present Arteria, a computational automation system for sequencing core facilities. This system has been adopted by multiple facilities and has been used to analyze thousands of samples. In Study V we developed CheckQC, a program that provides automated quality control of Illumina sequencing runs. These tools make scaling up MPS less labour intensive, a key to unlocking the full future potential of genomics.

The tools, and data presented here are a valuable contribution to the scientific community. Collectively they showcase the power of MPS and genomics to bring about new knowledge of human health and disease.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 68
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1492
Keywords
Acute Lymphoblastic Leukemia (ALL), RNA-Sequencing, Bioinformatics, Pooling, Whole Genome Sequencing
National Category
Medical Genetics Cancer and Oncology Hematology Computer Systems Bioinformatics (Computational Biology)
Research subject
Medical Genetics; Bioinformatics
Identifiers
urn:nbn:se:uu:diva-358289 (URN)978-91-513-0428-1 (ISBN)
Public defence
2018-10-19, E10:1307-1309 (Trippelrummet), Navet, Biomedicinskt centrum, Husargatan 3, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2018-09-20 Created: 2018-08-27 Last updated: 2018-10-02

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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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