Genome-wide Discovery of Somatic Coding and Noncoding Mutations in Pediatric Endemic and Sporadic Burkitt Lymphoma

Blood. 2019 Mar 21;133(12):1313-1324. doi: 10.1182/blood-2018-09-871418. Epub 2019 Jan 7.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Biomarkers, Tumor / genetics*
  • Burkitt Lymphoma / genetics*
  • Burkitt Lymphoma / pathology
  • Burkitt Lymphoma / virology
  • Child
  • Child, Preschool
  • Cohort Studies
  • Cytidine Deaminase / genetics
  • Epstein-Barr Virus Infections / complications*
  • Epstein-Barr Virus Infections / genetics
  • Epstein-Barr Virus Infections / virology
  • Female
  • Follow-Up Studies
  • Genes, Immunoglobulin*
  • Genome, Human*
  • Herpesvirus 4, Human / isolation & purification
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Mutation*
  • Phenotype
  • Prognosis
  • Transcriptome*
  • Young Adult

Substances

  • Biomarkers, Tumor
  • AICDA (activation-induced cytidine deaminase)
  • Cytidine Deaminase