Open AccessSubtype-specific and co-occurring genetic alterations in B-cell non-Hodgkin lymphoma
Author(s) -
Man Chun John,
Saber Tadros,
Alyssa Bouska,
Tayla B. Heavican,
Haopeng Yang,
Qing Deng,
Dalia Moore,
Ariz Akhter,
Keenan T. Hartert,
Neeraj Jain,
Jordan Showell,
Sreejoyee Ghosh,
Lesley Street,
Marta B. Davidson,
Christopher D. Carey,
Joshua W.D. Tobin,
Deepak Perumal,
Julie M. Vose,
Matthew A. Lunning,
Aliyah R. Sohani,
Benjamin J. Chen,
Shan Buckley,
Loretta J. Nastoupil,
R. Eric Davis,
Jason R. Westin,
Nathan Fowler,
Samir Parekh,
Maher K. Gandhi,
Sattva S. Neelapu,
Douglas Stewart,
Kapil N. Bhalla,
Javeed Iqbal,
Timothy C. Greiner,
Scott J. Rodig,
Adnan Mansoor,
Michael R. Green
Publication year - 2021
Publication title -
haematologica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.782
H-Index - 142
eISSN - 1592-8721
pISSN - 0390-6078
DOI - 10.3324/haematol.2020.274258
Subject(s) - lymphoma , mantle cell lymphoma , biology , follicular lymphoma , comparative genomic hybridization , cancer research , b cell , malignancy , non hodgkin's lymphoma , b cell lymphoma , genetics , gene , immunology , genome , antibody
B-cell non-Hodgkin’s 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 (DLBCL) have been comprehensively interrogated at the genomic level. But rarer subtypes such as mantle cell lymphoma (MCL) remain sparsely 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 DLBCL, MCL, follicular lymphoma (FL), and Burkitt lymphoma (BL). We identified conserved hallmarks of B-NHL that were deregulated in the majority of tumor from each subtype, including the frequent genetic deregulation of the ubiquitin proteasome system (UPS). 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.