Genetic Subgroups Inform on Pathobiology in Adult and Pediatric Burkitt Lymphoma

Abstract

Burkitt lymphoma (BL) accounts for the majority of pediatric non-Hodgkin lymphomas (NHL) and is relatively rare but significantly more lethal when diagnosed in adults. The global incidence is highest in Sub-Saharan Africa, where Epstein-Barr virus (EBV) positivity is observed in 95% of all tumors. Both pediatric (pBL) and adult (aBL) cases are known to share some driver mutations, for example MYC translocations, which are seen in > 90% of cases. Sequencing efforts have identified many common somatic alterations that cooperate with MYC in lymphomagenesis with approximately 30 significantly mutated genes (SMG) reported thus far. Recent analyses revealed non-coding mutation patterns in pBL that were attributed to aberrant somatic hypermutation (aSHM). We sought to identify genomic and molecular features that may explain clinical disparities within and between aBL and pBL in an effort to delineate BL subtypes that may allow for the stratification of patients with shared pathobiology. Through comprehensive sequencing of BL genomes, we found additional SMGs, including more genetic features that associate with tumor EBV status, and established three new genetic subgroups that span pBL and aBL. Direct comparisons between pBL and aBL revealed only marginal differences and the mutational profiles were consistently better explained by EBV status. Using an unsupervised clustering approach to identify subgroupings within BL and diffuse large B-cell lymphoma (DLBCL), we have defined three genetic subgroups that predominantly comprise BL tumors. Akin to the recently defined DLBCL subgroups, each BL subgroup is characterized by combinations of common driver mutations and non-coding mutations caused by aSHM. Two of these subgroups and their prototypical genetic features (ID3 and TP53) had significant associations with patient outcomes that were different among the aBL and pBL cohorts. These findings highlight not only a shared pathogenesis between aBL and pBL, but also establish genetic subtypes within BL that serve to delineate tumors with distinct molecular features, providing a new framework for epidemiological studies, and diagnostic and therapeutic strategies.

Burkitt Lymphoma Incidence in Five Continents

“…This idea was also supported by findings that somatic mutations in ID3, TCF3, CCND3, and SOX11 genes were detected more frequently in pediatric BL patients than adult cases [82], which agrees with the EBV data discussed above. Independent support for this idea has been reported in a study of 230 BL cases from Africa, the US, Germany, and Brazil, which showed distinct somatic mutations in pediatric cases (ARID1A) versus adult cases (TET2) [84]. A promising area of research is to elucidate the molecular basis of multimodality of BL in regional and global datasets.…”

Clinical relevance of molecular characteristics in Burkitt lymphoma differs according to age

“…Due to MYC mutation, proliferation and apoptosis are uncoupled, consequently proliferation is stimulated and apoptosis abrogated. Deregulation and progression of cell cycle is augmented by several mutations, for example by a mutation in CCND3, TCF3, ID3, and TP53 9,26,34,35 .…”

“…The relevance of this finding is underlined by the findings from refs. 35,51 , which were published during the revision of this study 36,51 . Both studies show the negative impact of TP53 mutations on survival.…”

Genomic profiling for clinical decision making in lymphoid neoplasms

“…Some of the emerging genetic subgrouping systems for lymphomas rely on the presence of specific driver mutations (including SVs and CNAs) and patterns of SHM. 187,[409][410][411] SVs involving an oncogene and an active regulatory element causing ectopic oncogene expression (eg, BCL2) or those forming a functional fusion gene (eg, NPM1::ALK) can be diagnostic, prognostic, or predictive for targeted therapies. For oncogenes having promiscuous rearrangement partners (eg, MYC, BCL6), the identity of partners may have a differential influence on prognosis.…”