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Abschlussbericht Für Vorhaben 3609S30013

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Abschlussbericht Für Vorhaben 3609S30013 Ressortforschungsberichte zur kerntechnischen Sicherheit und zum Strahlenschutz Untersuchungen zum Zusammenwirken umweltbedingter Risikofaktoren mit genetischen und weiteren endogenen Faktoren bei der Entstehung von Leukämie im Kindesalter Teilvorhaben 1; Pilotstudie: Sequenzierung und bioinformatische Auswertung - Vorhaben 3611S70014 Auftragnehmer: Universitätsklinikum Schleswig-Holstein - Campus Kiel M. Stanulla A. Borkhardt C. Eckert J. Korbel M. Schrappe M.-L. Yaspo A. Franke Das Vorhaben wurde mit Mitteln des Bundesministeriums für Umwelt, Naturschutz, Bau und Reaktorsicherheit (BMUB) und im Auftrag des Bundesamtes für Strahlenschutz (BfS) durchgeführt. Dieser Band enthält einen Ergebnisbericht eines vom Bundesamt für Strahlenschutz im Rahmen der Ressortforschung des BMUB (UFOPLAN) in Auftrag gegebenen Untersuchungsvorhabens. Verantwortlich für den Inhalt sind allein die Autoren. Das BfS übernimmt keine Gewähr für die Richtigkeit, die Genauigkeit und Vollständigkeit der Angaben sowie die Beachtung privater Rechte Dritter. Der Auftraggeber behält sich alle Rechte vor. Insbesondere darf dieser Bericht nur mit seiner Zustimmung ganz oder teilweise vervielfältigt werden. Der Bericht gibt die Auffassung und Meinung des Auftragnehmers wieder und muss nicht mit der des BfS übereinstimmen. BfS-RESFOR-103/15 Bitte beziehen Sie sich beim Zitieren dieses Dokumentes immer auf folgende URN: urn:nbn:de:0221-2015012912280 Salzgitter, Januar 2015 - 1 - Untersuchungen zum Zusammenwirken umweltbedingter Risikofaktoren mit genetischen und weiteren endogenen Faktoren bei der Entstehung von Leukämie im Kindesalter - 2 - Pilotstudie: Sequenzierung und bioinformatische Auswertung von kindlichen Leukämie-Fällen (Akute lymphoblastische Leukämie/ALL) Martin Stanulla,1 Arndt Borkhardt,2 Cornelia Eckert,3 Jan Korbel,4 Martin Schrappe,1 Marie-Laure Yaspo,5 Andre Franke6 1 Klinik für Allgemeine Pädiatrie, Universitätsklinikum Schleswig Holstein, Campus Kiel, und Christian Albrechts Universität zu Kiel, 24105 Kiel; 2 Klinik für Kinder-Onkologie, -Hämatologie und Klinische Immunologie, Universitätsklinikum Düsseldorf, 40225 Düsseldorf; 3 Klinik für Pädiatrie mit Schwerpunkt Onkologie und Hämatologie, Charité Universi­ tätsmedizin, 13353 Berlin; 4 European Molecular Biology Laboratory (EMBL), 69117 Heidelberg; 5 Max Planck Institut für Molekulare Genetik, 14195 Berlin; 6 Institut für Klinische Molekularbiologie und 8Medizinische Klinik I, Universitätsklini- kum Schleswig Holstein, Campus Kiel, und Christian Albrechts Universität zu Kiel, 24105 Kiel - 3 - Inhalt: Seite A Zusammenfassung/Summary 4 B Projekthintergrund 8 C Methoden 34 D Ergebnisse 45 E Diskussion 74 F Literatur 79 G Anhang 91 - 4 - A Zusammenfassung/Summary Die akute lymphoblastische Leukämie (ALL) ist eine bösartige Erkrankung des Knochenmarks, bei der lymphoide Vorläuferzellen in einem frühen Differenzierungsstadium in ihrer Ausreifung blockiert sind. Die Ursachen, die der ALL zugrunde liegen, sind zum überwiegenden Teil nicht bekannt. Nur ein kleiner Prozentsatz der Fälle ist durch vererbbare genetische Prädisposition erklärbar, wie sie sich etwa für das Down-Syndrom und weitere Erkrankungen beschrieben findet. Diesen genetischen Konstellationen höherer Penetranz stehen seit kurzem auch erste Informationen aus genomweiten Assoziationsstudien gegenüber, in denen gewöhnliche Varianten in den Genen IKZF1, ARIDB5, CEBPE, TP63, PTPRJ, PIP4K2 und GATA3 mit dem Risiko einer ALL assoziiert werden konnten. Weiterhin sind zahlreiche somatische genetische Aberrationen der ALL charakterisiert worden und es kommen ständig neue hinzu. Auch zur Sequenz des Erwerbs solcher genetischer Veränderungen ist dazugelernt worden. Aus molekularen Untersuchungen an zum Neugeborenen-Screening archivierten Guthrie-Karten von eineiigen, später an ALL erkrankten Zwillingen konnte durch das Auffinden identischer Genfusionssequenzen leukämiespezifischer chromosomaler Translokationen (z.B. ETV6-RUNX1) rückgeschlossen werden, dass die ersten leukämieassoziierten genetischen Veränderungen sehr früh – nämlich bereits in utero – erworben werden können. Das Muster der letztlich in der klinisch apparenten Leukämie angesammelten genetischen Veränderungen lässt sich dabei nicht immer logisch ableiten. Seit kurzer Zeit ist es durch den enormen technischen Fortschritt im Bereich neuer Sequenzier-technologien möglich, das gesamte Erbgut auf seinen verschiedenen Ebenen zu analysieren. Diese Technologie sollte im vorliegenden Projekt an zehn ausgewählten ALLs systematisch angewendet werden, um Veränderungen des Genoms, des Exoms, des Transkriptoms, des Methyloms und des miRNoms in umfassender Art und Weise zu analysieren. Für die Analysen sind fünf B-Zell-Vorläufer- ALLs mit einer chromosomalen Translokation t(17;19), die zu einer Genfusion des Hepatic leukemia factor (HLF)-Gens mit dem TCF3-Gen führt, sowie fünf B-Zell-Vorläufer-ALLs mit einer chromosomalen Translokation t(1;19), die zu einer Genfusion des Pre-B cell leukemic homeobox1 (PBX1)-Gens mit dem TCF3­ - 5 - Gen führt, ausgewählt worden. Weiterhin sind rekurrente somatische Veränderungen, die in den initialen Sequenzieranalysen detektiert wurden, in weiteren ALL-Patientenproben validiert worden. Es wurden Read-Alignments für Genome und Exome gegen das humane Referenzgenom und Annotation und Klassifizierung der Varianten durchgeführt. Strukturelle Varianten wurden mittels Sequenzpaaranalyse, Sequenztiefenanalyse, Sequenzaufspaltungsanalyse und Sequenzassemblierung untersucht. Methylomdaten wurden mittels spezieller Algorithmen, unter Berücksichtigung der Bisulfitkonvertierung, auf die Zielregion im Referenzgenom („restriction specific target enrichment“) abgebildet - anschließend wurde der Grad der DNA-Methylierung an Cytosin-Basen bestimmt. Transkriptomsequenzen wurden nach Kartierung auf das Referenzgenom analysiert, es wurden Expressionsprofile und Pathwayanalysen für jede Probe durchgeführt sowie neben Sequenzvarianten auch eine umfassende Analyse der Spleißvarianten. TCF3-HLF-positive ALLs zeichneten sich in diesen Analysen durch eine Häufung an strukturellen Aberrationen betreffend Gene mit Bedeutung für die lymphoide Differenzierung und aktivierende RAS-Signalweg-Mutationen aus, die in TCF3­ PBX1-positiven ALLs nahezu abwesend waren. Weiterhin zeichnete sich die TCF3­ HLF-positive ALL durch eine stammzellnahe Trankriptsignatur gegenüber der TCF3­ PBX1-positiven ALL aus. In beiden Gruppen konnten Aberrationen des nicht- translozierten TCF3-Allels detektiert werden. Eine dieser Aberrationen war eine Einzelnukleotidvariante, die in weiterführenden Analysen als seltenes, rekurrentes Merkmal der ALL im Kindesalter neu beschrieben werden konnte. Insgesamt lassen diese Ergebnisse erkennen, dass neue Sequenziertechnologien detaillierte Einblicke in das Zusammenspiel molekularer Aberration bei der ALL im Kindesalters erlauben und damit eine Grundlage für ein besseres Verständnis ihrer Pathobiologie und die Entwicklung neuer, stärker individuell ausgerichteter Therapieansätze schaffen . Acute lymphoblastic leukemia (ALL) is a malignant disease of the bone marrow, characterized by an early-stage differentiation block of lymphoid progenitor cells. For the most part, causes of ALL are unknown. Only a small percentage of cases can be explained by heritable genetic predisposition, as it is described for Down's syndrome - 6 - and other diseases. This genetic constellation of higher penetrance was recently complemented with information from genome-wide association studies. These studies decribed common variants in the genes IKZF1, ARIDB5, CEBPE, TP63, PTPRJ, PIP4K2, and GATA3 to be associated with the risk of ALL. Furthermore, numerous somatic genetic aberrations of ALL have been characterized. Also, in which sequence genetic changes are acquired has been learned. Molecular studies on Guthrie cards in identical twins later diagnosed with ALL demonstrated identical sequences at chromosomal translocation breakpoints (e.g., ETV6-RUNX1). Through this, it could be inferred that the first leukemia-associated genetic changes occur already in utero. The pattern of accumulated lesions in the clinically apparent leukemia, however, often cannot be logically deduced. Recently, by the enormous technical progress in the field of new sequencing technologies, it became possible to analyze the entire genome at its various levels. In the present project, this technology was applied to systematically and comprehensively analyze ten selected ALLs for changes in the genome, exome, transcriptome, methylome, and miRNom. Five B-cell precursor ALLs with a chromosomal translocation t(17;19), leading to a gene fusion of hepatic leukemia factor (HLF) with TCF3, and five B-cell precursors ALLs with a chromosomal translocation t(1;19), leading to a gene fusion of the pre-B homeobox 1 (PBX1) gene with TCF3 gene, were selected. Furthermore, recurrent somatic changes detected in the initial sequencing analyses were validated in additional ALL patient samples. Initially, read alignments were performed for genomes and exomes against human genome reference data, nucleotide variants were annotated and classified. Structural variants were examined by paired-end, read depth, split-read, and sequence assembly analyses. Methylome data were mapped to target regions of the reference genome by means of special algorithms taking into account the bisulfate conversion ("restriction specific target enrichment"). This was followed by determination of the degree of DNA methylation at cytosine bases. Transcriptome sequences
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