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Identification of somatic variants by targeted sequencing of pooled cancer samples
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. (Syvänen)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. (Syvänen)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. (Syvänen)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. (Syvänen)
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(English)Manuscript (preprint) (Other academic)
National Category
Medical Genetics
Research subject
Medical Genetics
Identifiers
URN: urn:nbn:se:uu:diva-269752OAI: oai:DiVA.org:uu-269752DiVA: diva2:885114
Available from: 2015-12-18 Created: 2015-12-18 Last updated: 2016-02-02
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)
Opponent
Supervisors
Available from: 2016-01-26 Created: 2015-12-18 Last updated: 2016-02-12Bibliographically approved

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Lindqvist, Carl Mårten

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