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Advances in Genomics: Tools Finally Opening the Molecular Secrets of Burkitt Lymphoma

PhD Trainee  Ticketed Session
Sponsor: Scientific
Program: Spotlight Sessions
Monday, December 11, 2023: 10:30 AM-11:45 AM
Grand Hall D (Manchester Grand Hyatt San Diego)
Co-chairs:
Ryan D Morin, PhD, 6226 and Ludmila Prokunina-Olsson, PhD, National Cancer Institute
Disclosures:
No relevant conflicts of interest to declare.
Burkitt lymphoma (BL) accounts for many cases of pediatric cancer in malaria-endemic areas where tumors typically harbor Epstein-Barr virus (EBV). Outcomes of BL remain dismal in these settings, with patient care confounded by inadequate access to timely diagnosis, staging, and facilities for specialized cancer treatment. 

Dr. Morin will discuss how comprehensive sequencing has delineated the mutations that contribute to lymphomagenesis and the relationship between EBV positivity and unique genetic and mutation patterns, thereby affirming the important role of EBV in BL biology. His group demonstrated that BL is driven by similar genetic alterations in pediatric and adult cases. Using a combination of mutations, his team showed that BL can be divided into three main subgroups, each with distinct combinations of driver mutations. By applying genome-wide methylation profiling to these same samples, Dr. Morin’s team explored the interplay between genetics and global patterns of CpG methylation. This revealed two robust epitypes of BL that span the existing genetic and molecular divisions, namely HyperBL and HypoBL. HyperBL is associated with hypermethylation and has a higher mutation burden, elevated rates of aSHM and inferior outcomes and is more common in EBV+ cases. Hypermethylation of key BL genes such as ID3 was correlated with reduced expression, indicating methylation contributes to reduced tumor suppressor function. These results support the importance of incorporating genetic, epigenetic and gene expression features in molecular profiling. Further refinement and validation of these subdivisions may lead to new therapeutic strategies that exploit the unique molecular features of each group. 

Dr. Prokunina-Olsson will discuss the results from the first genome wide association study (GWAS) of BL to be conducted in children enrolled in Uganda, Kenya, Tanzania, and Malawi. The results include a significant association between BL risk and mosaic chromosomal alterations (mCAs) and with a locus at 21q22.12 near RUNX1. This work opens new directions to explore the role of host genetic architecture in BL risk and the need for GWAS in expanded populations. Dr. Prokunina-Olsson will also share some preliminary findings from ongoing mechanistic studies to elucidate the physiological and clinical impact of mosaic chromosomal alterations and germline variants in BL risk. 

Ryan D Morin, PhD

6226, Burnaby, BC, Canada

Ludmila Prokunina-Olsson, PhD

National Cancer Institute, Rockville, MD

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