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Whole-genome sequencing in subsets of chronic lymphocytic leukemia harboring stereotyped B-cell receptors
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
Università Vita-Salute San Raffaele, and Division of Experimental Oncology and Department of Onco-Hematology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Department of Immunology, Erasmus MC, University Medical Center Rotterdam, the Netherlands.
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(English)Manuscript (preprint) (Other academic)
National Category
Medical Genetics
URN: urn:nbn:se:uu:diva-302024OAI: oai:DiVA.org:uu-302024DiVA: diva2:956006
Swedish Cancer SocietySwedish Research Council
Available from: 2016-08-28 Created: 2016-08-28 Last updated: 2016-08-29
In thesis
1. Exploring next-generation sequencing in chronic lymphocytic leukemia
Open this publication in new window or tab >>Exploring next-generation sequencing in chronic lymphocytic leukemia
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Next-generation sequencing (NGS) techniques have led to major breakthroughs in the characterization of the chronic lymphocytic leukemia (CLL) genome with discovery of recurrent mutations of potential prognostic and/or predictive relevance. However, before NGS can be introduced into clinical practice, the precision of the techniques needs to be studied in better detail. Furthermore, much remains unknown about the genetic mechanisms leading to aggressive disease and resistance to treatment. Hence, in Paper I, the technical performance of a targeted deep sequencing panel including 9 genes was evaluated in 188 CLL patients. We were able to validate 143/155 (92%) selected mutations through Sanger sequencing and 77/82 mutations were concordant in a second targeted sequencing run, indicating that the technique can be introduced in clinical practice. In Paper II we screened 18 NF-κB pathway genes in 315 CLL patients through targeted deep sequencing which revealed a recurrent 4 base-pair deletion in the NFKBIE gene. Screening of NFKBIE in 377 additional cases identified the mutation in ~6% of all CLL patients. We demonstrate that the lesion lead to aberrant NF-κB signaling through impaired interaction with p65 and is associated with unfavorable clinical outcome. In Paper III we sought to delineate the genetic lesions that leads to relapse after fludarabine, cyclophosphamide, and rituximab treatment. Through whole-exome sequencing of pre-treatment and relapse samples from 41 cases we found evidence of frequent selection of subclones harboring driver mutations and subsequent clonal evolution following treatment. We also detected mutations in the ribosomal protein RPS15 in 8 cases (19.5%) and characterization of the mutations through functional assays point to impaired p53 regulation in cells with mutated RPS15. Paper IV aimed at characterizing 70 patients assigned to three major subsets (#1, #2, and #4) through whole-genome sequencing. Besides recurrent exonic driver mutations, we report non-coding regions significantly enriched for mutations in subset #1 and #2 that may facilitate future molecular studies. Collectively, this thesis supports the potential of targeted sequencing for mutational screening of CLL in clinical practice, provides novel insight into the pathobiology of aggressive CLL, and demonstrates the clinical outcome and cellular effects of NFKBIE and RPS15 mutations. 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. 61 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1251
CLL, next-generation sequencing, clonal evolution, stereotypy, RPS15, NFKBIE
National Category
Medical Genetics
Research subject
Medical Genetics
urn:nbn:se:uu:diva-302026 (URN)978-91-554-9674-6 (ISBN)
Public defence
2016-10-14, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds v 20, Uppsala, 09:15 (English)
Available from: 2016-09-22 Created: 2016-08-29 Last updated: 2016-09-22

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