AbstractsBiology & Animal Science

Frequency and relevance of genetic alterations of the ID3-TCF3-CCND3 pathway in pediatric mature B-cell Non-Hodgkin lymphoma

by Marius Rohde

Institution: Universität Giessen
Department: FB 11 - Medizin
Degree: PhD
Year: 2015
Record ID: 1105258
Full text PDF: http://geb.uni-giessen.de/geb/volltexte/2015/11369


B-cell Non-Hodgkin Lymphoma (B-NHL) is the most common type of Non-Hodgkin Lymphoma in childhood and adolescent cancer patients. B-NHL can be further classified into subtypes, with Burkitt lymphoma (BL) being the most common entity in pediatric patients. Recently published large-scale next-generation sequencing studies unveiled sets of recurrently mutated genes in tumor cells of pediatric and adult B-NHL patients and introduced functionally related Inhibitor of DNA 3 (ID3), Transcription Factor 3 (TCF3) and Cyclin D3 (CCND3) as potential drivers of BL lymphomagenesis. However, validation of these findings showed inconsistent mutation rates and assessment of clinical relevance was limited. In the present study frequency and relevance of mutations in ID3, TCF3 and CCND3 were analyzed within a well-defined cohort of 84 uniformly diagnosed and treated pediatric B-NHL patients. Mutation frequency was 77% (ID3), 13% (TCF3) and 37% (CCND3) in BL (including Burkitt leukemia) and mutations remained almost exclusive for MYC rearrangement positive cases. ID3 mutations were detected in remarkably higher frequency than previously published. There was no clear association between mutation status and outcome, but certain concurrent mutations where enriched in more advanced stages of the disease. As a control group of a related malignancy, 96 samples from precursor B-cell leukemia (pB-ALL) patients were also analyzed for ID3 mutations. As expected, no mutations were found, but two cases showed genomic variants in ID3. Interestingly, for one of these cases it was possible to show a genetic alteration involving MYC, which is usually a key feature of BL. We conclude, that almost 90% of MYC rearrangement positive B-NHL harbored mutations in at least one of the investigated genes and therefore this study promotes the corresponding pathway to play an essential role in BL and especially in pediatric cases. B-Zell Non-Hodgkin Lymphome (B-NHL) sind der häufigste Typ von Non-Hodgkin Lymphomen bei Kindern und Jugendlichen mit malignen Krebserkrankungen. B-NHL können weiter in Subtypen klassifiziert werden, in denen das Burkitt Lymphom (BL) die häufigste Entität bei Kindern und Jugendlichen darstellt. In der jüngsten Zeit haben Ganzgenomsequenzierungen von Tumorproben eine Liste von besonders häufig mutierten Genen in B-NHL von pädiatrischen und erwachsenen Patienten gezeigt. Unter anderem wurden die funktionell zusammenhängenden Kandidaten ID3, TCF3 und CCND3 als mögliche Antreiber der Lymphompathogenese bei BL beschrieben. Allerdings zeigten sich in verschiedenen Studien inkonsistente Mutationsfrequenzen und die Untersuchung der klinischen Bedeutung war limitiert. In dieser Studie wurden die Frequenz und Relevanz von Mutationen in den drei Kandidatengenen ID3, TCF3 und CCND3 in einer klar definierten Kohorte von 84 einheitlich diagnostizierten und behandelten pädiatrischen Fällen mit B-NHL untersucht. In BL (inklusive Burkitt Leukämie) waren die Mutationsfrequenzen 77% (ID3), 13% (TCF3) und 37% (CCND3) und in Bezug auf die Gesamtkohorte…