Journal
HAEMATOLOGICA
Volume 107, Issue 3, Pages 690-701Publisher
FERRATA STORTI FOUNDATION
DOI: 10.3324/haematol.2020.274258
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Funding
- NCI [R01CA201380]
- Nebraska Department of Health and Human Services [LB506 2016-17]
- NCI cancer center support grants [P30 CA016672, P30 CA036727]
- Leukemia and Lymphoma Society
- Andrew Sabin Family Foundation Fellow award
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This study comprehensively analyzed the genomic landscapes of multiple B-cell non-Hodgkin lymphoma (B-NHL) subtypes, and identified common features and subtype-specific patterns of genetic alterations. The study also revealed potential patterns of genetic cooperation that contribute to lymphomagenesis, providing important insights into the pathogenesis of B-NHL.
B-cell non-Hodgkin lymphoma (B-NHL) encompasses multiple clinically and phenotypically distinct subtypes of malignancy with unique molecular etiologies. Common subtypes of B-NHL, such as diffuse large B-cell lymphoma, have been comprehensively interrogated at the genomic level, but rarer subtypes, such as mantle cell lymphoma, remain less extensively characterized. Furthermore, multiple B-NHL subtypes have thus far not been comprehensively compared using the same methodology to identify conserved or subtype-specific patterns of genomic alterations. Here, we employed a large targeted hybrid-capture sequencing approach encompassing 380 genes to interrogate the genomic landscapes of 685 B-NHL tumors at high depth, including diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, and Burkitt lymphoma. We identified conserved hallmarks of B-NHL that were deregulated in the majority of tumors from each subtype, including frequent genetic deregulation of the ubiquitin proteasome system. In addition, we identified subtype-specific patterns of genetic alterations, including clusters of co-occurring mutations and DNA copy number alterations. The cumulative burden of mutations within a single cluster were more discriminatory of B-NHL subtypes than individual mutations, implicating likely patterns of genetic cooperation that contribute to disease etiology. We therefore provide the first cross-sectional analysis of mutations and DNA copy number alterations across major B-NHL subtypes and a framework of co-occurring genetic alterations that deregulate genetic hallmarks and likely cooperate in lymphomagenesis.
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