Pathognomonic and epistatic genetic alterations in B-cell non-Hodgkin lymphoma

Ma, M. C. J.; Tadros, S.; Bouska, A.; Heavican, T.; Yang, H.; Deng, Q.; Moore, D.; Akhter, A.; Hartert, K.; Jain, N.; Showell, J.; Ghosh, S.; Street, L.; Davidson, M.; Carey, C.; Tobin, J.; Perumal, D.; Vose, J.; Lunning, M.; Sohani, A.; Chen, B.; Buckley, S.; Nastoupil, L.; Davis, R. E.; Westin, J.; Fowler, N.; Parekh, S.; Gandhi, M.; Neelapu, S.; Stewart, D.; Iqbal, J.; Rodig, S.; Mansoor, A.; Green, M.

doi:10.1101/674259

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bioRxiv · 10.1101/674259

Pathognomonic and epistatic genetic alterations in B-cell non-Hodgkin lymphoma

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Abstract

B-cell non-Hodgkins 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.

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Ma, M. C. J., Tadros, S., Bouska, A., Heavican, T., Yang, H., Deng, Q., Moore, D., Akhter, A., Hartert, K., Jain, N., Showell, J., Ghosh, S., Street, L., Davidson, M., Carey, C., Tobin, J., Perumal, D., Vose, J., Lunning, M., Sohani, A., Chen, B., Buckley, S., Nastoupil, L., Davis, R. E., Westin, J., Fowler, N., Parekh, S., Gandhi, M., Neelapu, S., Stewart, D., Iqbal, J., Rodig, S., Mansoor, A., Green, M.. 2019-06-19. Pathognomonic and epistatic genetic alterations in B-cell non-Hodgkin lymphoma. https://doi.org/10.1101/674259

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