Genome-wide discovery of somatic coding and noncoding mutations in pediatric endemic and sporadic Burkitt lymphoma

Abstract

Although generally curable with intensive chemotherapy in resource-rich settings, Burkitt lymphoma (BL) remains a deadly disease in older patients and in sub-Saharan Africa. Epstein-Barr virus (EBV) positivity is a feature in more than 90% of cases in malaria-endemic regions, and up to 30% elsewhere. However, the molecular features of BL have not been comprehensively evaluated when taking into account tumor EBV status or geographic origin. Through an integrative analysis of whole-genome and transcriptome data, we show a striking genome-wide increase in aberrant somatic hypermutation in EBV-positive tumors, supporting a link between EBV and activation-induced cytidine deaminase (AICDA) activity. In addition to identifying novel candidate BL genes such as SIN3A, USP7, and CHD8, we demonstrate that EBV-positive tumors had significantly fewer driver mutations, especially among genes with roles in apoptosis. We also found immunoglobulin variable region genes that were disproportionally used to encode clonal B-cell receptors (BCRs) in the tumors. These include IGHV4-34, known to produce autoreactive antibodies, and IGKV3-20, a feature described in other B-cell malignancies but not yet in BL. Our results suggest that tumor EBV status defines a specific BL phenotype irrespective of geographic origin, with particular molecular properties and distinct pathogenic mechanisms. The novel mutation patterns identified here imply rational use of DNA-damaging chemotherapy in some patients with BL and targeted agents such as the CDK4/6 inhibitor palbociclib in others, whereas the importance of BCR signaling in BL strengthens the potential benefit of inhibitors for PI3K, Syk, and Src family kinases among these patients.

Variation in the Human Leukocyte Antigen system and risk for endemic Burkitt lymphoma in northern Uganda

“…Despite its large size, our study is still small, so the findings need to be confirmed in a larger sample. Our results may also be misclassified because they are based on EBV‐defined BL phenotypes (Grande et al , ). Our adjustment for measures of malaria exposure (RDT, treatment history) may be overly conservative because our results are potentially biased to the null.…”

“…A role of autoimmunity and/or allergy in BL was suggested by findings that the odds of sporadic BL under age 50 years were decreased in those with a history of allergy or asthma in the International Lymphoma consortium (Mbulaiteye et al , ). It is also suggested by molecular data showing that BL tumours disproportionately use a small set of immunoglobulin heavy‐chain variable (IGHV) gene segments involved in autoreactivity (Bhat et al , ), such as IGHV4‐34 (Lombardo et al , ; Grande et al , ), and that some BL tumours secrete proteins against self‐antigens (Ng et al , ; Riboldi et al , ).…”

Aggressive desmoid fibromatosis in Kabuki syndrome: Expanding the tumor spectrum

“…Accordingly, the Epstein-Barr virus and the classic somatic t(8;14) translocation involving the oncogene MYC were identified in KS-associated Burkitt lymphomas (Table 1). 14,15 Limited data are available on somatic tumor testing in KS, but we suggest that affected individuals might be at increased risk of developing cancer due to additional somatic second hit mutations. Moreover, KMT2D haploinsufficiency per se might cause cell-type specific tumor-promoting effects.…”

“…As observed in similar conditions, somatic second hits might provide relevant contribution to drive the oncogenic machinery. Accordingly, the Epstein‐Barr virus and the classic somatic t(8;14) translocation involving the oncogene MYC were identified in KS‐associated Burkitt lymphomas (Table ) . Limited data are available on somatic tumor testing in KS, but we suggest that affected individuals might be at increased risk of developing cancer due to additional somatic second hit mutations.…”

Two pathways of p27Kip1degradation are required for murine lymphoma driven by Myc and EBV latent membrane protein 2A

“…The mechanisms driving BL tumors can differ drastically depending on the presence or absence of EBV. EBV-positive BL genomes carry fewer, and distinct, driver mutations compared to EBV-negative(29). Previous studies, including by our group, have shown that LMP2A accelerates tumor development in combination with dysregulated Myc, obviating the need for mutations in the ARF-Mdm2-p53 pathway(22, 23).…”