John Ma, Man ChunChen, Benjamin J.Green, Michael R.2022-08-232022-08-232019-06-192019-06-20<p>bioRxiv 674259; doi: https://doi.org/10.1101/674259. <a href="https://doi.org/10.1101/674259" target="_blank">Link to preprint on bioRxiv service.</a></p>10.1101/674259https://hdl.handle.net/20.500.14038/29385<p>Full author list omitted for brevity. For the full list of authors, see article.</p>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 (DLBCL) have been comprehensively interrogated at the genomic level, but other less common subtypes such as mantle cell lymphoma (MCL) remain sparsely characterized. Furthermore, multiple B-NHL subtypes have thus far not been comprehensively compared 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 755 B-NHL tumors at high depth; primarily including DLBCL, MCL, follicular lymphoma (FL), and Burkitt lymphoma (BL). We identified conserved hallmarks of B-NHL that were deregulated across major subtypes, such as 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 that are pathognomonic. The cumulative burden of mutations within a single cluster were more significantly discriminatory of B-NHL subtypes than individual mutations, implicating likely patterns of genetic epistasis that contribute to disease etiology. We therefore provide a framework of co-occurring mutations that deregulate genetic hallmarks and likely cooperate in lymphomagenesis of B-NHL subtypes.en-USThe copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It is made available under a CC-BY-NC-ND 4.0 International license.http://creativecommons.org/licenses/by-nc-nd/4.0/B-cell non-Hodgkin lymphomagenetic alterationspathologyubiquitin proteasome systemlymphomagenesisB-NHLAmino Acids, Peptides, and ProteinsCancer BiologyGenetic PhenomenaGenomicsHemic and Lymphatic DiseasesNeoplasmsPathologyPreprinthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=2627&amp;context=faculty_pubs&amp;unstamped=1https://escholarship.umassmed.edu/faculty_pubs/161514778189faculty_pubs/1615