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

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RohdeMarius_2015_02_16.pdf (4.72 MB)

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2013

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DOI:
http://dx.doi.org/10.22029/jlupub-14133

Abstract

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.

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