Relevance of ID3-TCF3-CCND3 pathway mutations in pediatric aggressive B-cell lymphoma treated according to the non-Hodgkin Lymphoma Berlin-Frankfurt-Münster protocols

Abstract

Mature B-cell non-Hodgkin lymphoma is the most common subtype of non-Hodgkin lymphoma in childhood and adolescence. B-cell non-Hodgkin lymphomas are further classified into histological subtypes, with Burkitt lymphoma and Diffuse large B-cell lymphoma being the most common subgroups in pediatric patients. Translocations involving the MYC oncogene are known as relevant but not sufficient for Burkitt lymphoma pathogenesis. Recently published large-scale next-generation sequencing studies unveiled sets of additional recurrently mutated genes in samples of pediatric and adult B-cell non-Hodgkin lymphoma patients. ID3, TCF3 and CCND3 are potential drivers of Burkitt lymphomagenesis. In the study herein, frequency and clinical relevance of mutations in ID3, TCF3 and CCND3 were analyzed within a well-defined cohort of 84 uniformly diagnosed and treated pediatric B-cell non-Hodgkin lymphoma patients of the Berlin-Frankfurt-Münster group. Mutation frequency was 78% (ID3), 13% (TCF3) and 36% (CCND3) in Burkitt lymphoma (including Burkitt leukemia). ID3 and CCND3 mutations were associated with more advanced stages of the disease in MYC rearrangement positive Burkitt lymphoma. In conclusion, ID3-TCF3-CCND3 pathway genes are mutated in more than 88% of MYC-rearranged pediatric B-cell non-Hodgkin lymphoma and the pathway may represent a highly relevant second hit of Burkitt lymphoma pathogenesis, especially in children and adolescents.

Figure 1.

ID3 gene plot with annotated mutations of the study cohort. ID3 coding region of exon 1 is illustrated with single base-pair substitutions on the upper and more complex alterations (insertions, deletions, InDels, duplications) on the lower site. Substitutions resulting in a nonsense mutation are depicted in red. Hatched bars delineate deletions and InDels, dotted bars characterize insertions and duplications. Each mutation is labeled with a correspondent description on the genomic and protein level, as well as the absolute number of occurrences in brackets. The functional helix-loop-helix domain is mapped according to UniProt (Q02535).

Figure 2.

Overview of B-NHL patient sequencing results on ID3, TCF3 and CCND3. Reference diagnosis according to NHL-BFM study. Red block indicates a case with mutation, black block indicates wild-type. MYC rear.: MYC status as reported in the study database; +: MYC rearrangement positive; -: MYC rearrangement negative; o: MYC status unknown. ∗No reference pathology review available. Diagnosis according to study center review. ^†No reference diagnosis available. Diagnosis according to local pathology report. ^‡MYC FISH analysis not available. However, MYC-Ig PCR report was positive for MYC rearrangement. BL: Burkitt lymphoma; B-AL: Burkitt leukemia; DLBCL: Diffuse large B-cell lymphoma; B-NHL nfc: B-NHL unclassifiable, with features intermediate between BL and DLBCL.

Figure 3.

ID3, TCF3, Cyclin D3 pathway with frequencies of respective mutations in MYC rearrangement positive BL. BL with positive MYC translocation had mutations in at least one of the three investigated candidate genes in 89%, representing affection of the ID3-TCF3-CCND3 pathway in the vast majority of pediatric BL cases.