Age-related heterogeneity of Burkitt lymphoma: response to Mbulaiteye and Anderson.

Abstract

Mbulaiteye and Anderson emphasize that the age-related heterogeneity between paediatric versus adult Burkitt lymphoma (BL) that we detected at the genetic level (Havelange et al, 2016) has been previously highlighted by epidemiological studies (Mbulaiteye et al, 2010, 2012, 2014). At the same time, the authors claim that this heterogeneity of BL in several settings (clinical, epidemiogical) remains consistent with the definition of BL as an ‘isomorphic’ entity, because of its unique genetic hallmark characterized by MYC dysregulation through chromosomal translocations into the vicinity of immunoglobulin genes. We would like to highlight that MYC alterations have been identified in several other mature B-cell neoplasms and thus it is not pathognomonic sign for BL, even in association with characteristic morphological and immunohistochemical criteria. Moreover, MYC alteration alone is insufficient to trigger lymphomagenesis (Cai et al, 2015), and several cooperating genomic and epigenetic changes have been identified. As we described, the most common in BL is the inactivation of the TP53/P14ARF pathway needed for counteracting the pro-apoptotic effect of MYC (Havelange et al, 2016). The prognostic difference according to the age at diagnosis of BL is still present even when combining rituximab with short-intensive chemotherapy (Hoelzer et al, 2014; Minard-Colin et al, 2015; Giulino-Roth & Goldman, 2016). Thus, the age of the patient, and the general aging process, seems to impact BL biology. On the other hand, the impact of age on outcomes may also be explained by misclassification of high-grade B-cell lymphoma as BL and/or increased treatment toxicity of older patients compared to children. Therefore, we agree that it does not justify splitting BL into several sub-entities. We need more accurate, easy-to-use molecular biomarkers for clinical practice for (i) finer classification of BL, excluding the aggressive lymphomas, classified as high-grade B-cell lymphomas in the 2016 World Health Organization classification (Swerdlow et al, 2016), and (ii) better therapeutic stratification. We identified some novel potential biomarkers, including ID3 and CCND3 double-hit mutations and 18q21 copy neutral LOH, involving DCC in adult BL (Havelange et al, 2016). These should be confirmed in larger series. Recently, Broutier et al (2016) confirmed a tumour suppressor role for DCC in diffuse large B-cell lymphoma (DLBCL). They demonstrated that an imbalance in the netrin-1 (NTN1)/DCC expression ratio is associated with aggressive lymphoma, and DCC loss occurs in germinal centre DLBCL. These observations suggest that NTN1 targeting represents an attractive new therapeutic approach, especially in adult BL. This work was supported by grants from the Salus Sanguinis Foundation, the Fonds Maisin and the Société Française des Cancers de l'Enfant (SFCE) (Cent pour Sang la Vie), the Belgian Fonds National de la Recherche Scientifique (Télévie).