Epstein–Barr virus status of sporadic Burkitt lymphoma is associated with patient age and mutational features

Abstract

Sporadic Burkitt lymphoma (BL) is the most frequent tumour of children and adolescents but a rare subtype of lymphomas in adults. To date most molecular data have been obtained from lymphomas arising in the young. Recently, Epstein-Barr virus (EBV) positive and negative BL in young patients was shown to differ in molecular features. In the present study, we present a large age-overarching cohort of sporadic BL (n = 162) analysed by immunohistochemistry, translocations of MYC proto-oncogene, basic helix-loop-helix transcription factor (MYC), B-cell leukaemia/lymphoma 2 (BCL2) and B-cell leukaemia/lymphoma 6 (BCL6) and by targeted sequencing. We illustrate an age-associated inter-tumoral molecular heterogeneity in this disease. Mutations affecting inhibitor of DNA binding 3, HLH protein (ID3), transcription factor 3 (TCF3) and cyclin D3 (CCND3), which are highly recurrent in paediatric BL, and expression of sex determining region Y-box transcription factor 11 (SOX11) declined with patient age at diagnosis (P = 0Á0204 and P = 0Á0197 respectively). In contrast, EBV was more frequently detected in adult patients (P = 0Á0262). Irrespective of age, EBV-positive sporadic BL showed significantly less frequent mutations in ID3/TCF3/CCND3 (P = 0Á0088) but more often mutations of G protein subunit alpha 13 (GNA13; P = 0Á0368) and forkhead box O1 (FOXO1; P = 0Á0044) compared to EBV-negative tumours. Our findings suggest that among sporadic BL an EBV-positive subgroup of lymphomas increases with patient age that shows distinct pathogenic features reminiscent of EBVpositive endemic BL.

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

“…Here, we analyzed a large cohort of pediatric BL, based on high-quality DNA from fresh-frozen samples and an analysis pipeline validated by comprehensive Sanger sequencing, to have a calling sensitivity of 0.993 and specificity of 0.989. We systematically compared the mutational spectrum with adult BL as only limited information on the differences/similarities to pediatric cohorts are available 22 , 36 . In addition to the well-known MYC driver we identified recurrent SNV/indels in the ID3 - TCF3 - CCND3 pathway in 87% of cases as a potential second hit in our pediatric cohort.…”

Epstein–Barr virus positivity as a defining pathogenetic feature of Burkitt lymphoma subtypes

“…17 These findings suggest that an EBV-positive subgroup of lymphomas increases with patient age, demonstrating distinct pathogenic features reminiscent of EBV-positive eBL, providing further evidence of the differences between EBV-positive and EBV-negative BL in cases out of Africa. 17 Malaria and EBV are ubiquitous pathogens within the lymphoma belt of Africa. Plasmodium falciparum can repeatedly infect African children and may be responsible of chronic antigenic stimulation and consequent proliferation of latently EBV-infected B memory cells that may acquire MYC translocation before or when they re-enter the germinal centre.…”

“…Out of Africa, sBL is more common in adults and elderly patients where other infectious agents may be involved, 27 such as HIV and other pathogens, possibly related to immune senescence. Certainly, the epidemiology for BL is different among various geographic areas; more specifically in Africa and developing countries BL frequently affects children and is almost always EBV‐related, while in western countries it is more prevalent in adults and also widely linked with EBV in the elderly 17,28 . Consequently, based on increasing evidence, the epidemiological differences in BL reflect distinct pathogenesis of the disease, 29 and this well‐known aspect could be valid even for other lymphoproliferative processes, like Hodgkin lymphoma, which have the same visible epidemiological diversities 30–34 …”

“…In this issue of the British Journal of Haematology , a large age‐overarching cohort of sBL ( n = 162) was analysed by immunohistochemistry, translocations of MYC , B‐cell leukaemia/lymphoma 2 ( BCL2 ), BCL6 , and by targeted sequencing 17 . The Authors illustrate an age‐associated inter‐tumoral molecular heterogeneity in this disease.…”

“…In contrast, EBV was mainly detected in adult patients. Regardless of age, EBV‐positive sBL showed significantly less frequent mutations in ID3 / TCF3/CCND3 but more recurrent G protein subunit alpha 13 ( GNA13 ) and forkhead box O1 ( FOXO1 ) mutations when compared to EBV‐negative tumours 17 . These findings suggest that an EBV‐positive subgroup of lymphomas increases with patient age, demonstrating distinct pathogenic features reminiscent of EBV‐positive eBL, providing further evidence of the differences between EBV‐positive and EBV‐negative BL in cases out of Africa 17 …”