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The Mutational Landscape in Pediatric Acute Lymphoblastic Leukemia Deciphered by Whole Genome Sequencing
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, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Sweden.
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
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2015 (English)In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 36, no 1, 118-128 p.Article in journal (Refereed) Published
Abstract [en]

Genomic characterization of pediatric acute lymphoblastic leukemia (ALL) has identified distinct patterns of genes and pathways altered in patients with well-defined genetic aberrations. To extend the spectrum of known somatic variants in ALL, we performed whole genome and transcriptome sequencing of three B-cell precursor patients, of which one carried the t(12;21)ETV6-RUNX1 translocation and two lacked a known primary genetic aberration, and one T-ALL patient. We found that each patient had a unique genome, with a combination of well-known and previously undetected genomic aberrations. By targeted sequencing in 168 patients, we identified KMT2D and KIF1B as novel putative driver genes. We also identified a putative regulatory non-coding variant that coincided with overexpression of the growth factor MDK. Our results contribute to an increased understanding of the biological mechanisms that lead to ALL and suggest that regulatory variants may be more important for cancer development than recognized to date. The heterogeneity of the genetic aberrations in ALL renders whole genome sequencing particularly well suited for analysis of somatic variants in both research and diagnostic applications.

Place, publisher, year, edition, pages
2015. Vol. 36, no 1, 118-128 p.
National Category
Medical Genetics Cancer and Oncology
Identifiers
URN: urn:nbn:se:uu:diva-238183DOI: 10.1002/humu.22719ISI: 000347076700016PubMedID: 25355294OAI: oai:DiVA.org:uu-238183DiVA: diva2:770320
Available from: 2014-12-10 Created: 2014-12-10 Last updated: 2017-12-05Bibliographically approved
In thesis
1. Genomic characterization of pediatric acute lymphoblastic leukemia by deep sequencing
Open this publication in new window or tab >>Genomic characterization of pediatric acute lymphoblastic leukemia by deep sequencing
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Acute Lymphoblastic Leukemia (ALL) is the most common cancer in children, with close to 200 cases per year in the Nordic countries. Despite recent advances in modern chemotherapies, 20% of the ALL patients experience a relapse. ALL has traditionally been stratified into subtypes with different risk classification and therapy using large genomic aberrations such as translocations and aneuploidies. In recent years technological advances have enabled the detection of smaller genetic variants, such as point mutations and small insertions/deletions. This thesis focuses on the detection of these smaller variants and their potential impact for ALL.

The present work includes four studies. In the first study we investigated the effects of whole genome amplification and non-indexed pooling strategies to maximize the output of targeted sequencing. We found that whole genome amplified DNA is equivalent to genomic DNA when screening for point mutations in targeted sequencing data. We were able to accurately detect variants in non-indexed pools with up to ten samples. The second study describes further work on non-indexed pools where we pooled samples in an overlapping scheme and identified carriers of rare variants. The third study describes the whole genome and RNA sequencing of four patients with ALL and validated the results in a cohort of 168 additional ALL patients. In the whole genome sequenced patients we found somatic mutations in both known cancer driver-genes (KRAS and NOTCH1) and in putative driver-genes (KMT2D and KIF1B) after analysis of the additional ALL patients. We validated point mutations genome-wide and observed a large number of C>A mutations in one patient, in contrast to C>T mutations that are more common in cancer in general. The fourth study analyzed the same cohort as the third study and expanded the target to 872 genes linked to cancer, ALL or epigenetic regulation recorded in the literature. We found distinctive differences between BCP-ALL and T-ALL both in number and types of mutations. In addition we observed an association between mutations in the Notch signaling pathway and relapse.

These results will have an impact on future studies of cancer, and add another piece to the genetic puzzle of ALL.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. 35 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1170
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-269760 (URN)978-91-554-9444-5 (ISBN)
Public defence
2016-02-19, E10:1307-1309, Navet, BMC, Husargatan 3, Uppsala, Uppsala, 13:00 (English)
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Available from: 2016-01-26 Created: 2015-12-18 Last updated: 2016-02-12Bibliographically approved

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Lindqvist, C MårtenNordlund, JessicaJohansson, AnnaMoghadam, Behrooz TorabiRaine, AmandaÖvernäs, ElinDahlberg, JohanWahlberg, PerFrost, Britt-MarieLarsson, RolfPalle, JosefineLönnerholm, GudmarSyvänen, Ann-ChristineBerglund, Eva C

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Lindqvist, C MårtenNordlund, JessicaJohansson, AnnaMoghadam, Behrooz TorabiRaine, AmandaÖvernäs, ElinDahlberg, JohanWahlberg, PerFrost, Britt-MarieLarsson, RolfPalle, JosefineLönnerholm, GudmarSyvänen, Ann-ChristineBerglund, Eva C
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