3 years ago

Genetic and Functional Drivers of Diffuse Large B Cell Lymphoma

Genetic and Functional Drivers of Diffuse Large B Cell Lymphoma
Andrew M. Evens, Ashley D. Staton, Angela Collie, Eric Tse, Rex K.H. Au-Yeung, Estrid Høgdall, So Young Kim, Cassandra L. Love, David B. Dunson, Tiffany Tzeng, Andrew Clear, Mette Pedersen, Anupama Reddy, Sandeep S. Dave, Waseem Lone, Lanie E. Happ, Shawn Levy, Amy Chadburn, William W.L. Choi, Guojie Li, Leo Meriranta, Sirpa Leppa, Jenny Zhang, Jean L. Koff, Tushar Dave, Leo I. Gordon, Nishitha Reddy, Ora Paltiel, Shaoying Li, Evelyn Nguyen, Anne O. Gang, Nicholas S. Davis, Yok-Lam Kwong, Manju Sengar, Qiu Qin, Rachel Rempel, Magdalena B. Czader, Kristy L. Richards, Tayla B. Heavican, John Gribben, Eric D. Hsi, Alexander Waldrop, Andrea B. Moffitt, Neta Goldschmidt, Yuri Fedoriw, Marja-Liisa Karjalainen-Lindsberg, Peter Nørgaard, Maria Calaminici, Christopher R. Flowers, Leon Bernal-Mizrachi, Javeed Iqbal, Jyotishka Datta, Gopesh Srivastava, Elaine S. Jaffe, Annika Pasanen, Deepthi Rajagopalan, Jane Healy, Monika Pilichowska, Sarah L. Ondrejka

Summary

Diffuse large B cell lymphoma (DLBCL) is the most common form of blood cancer and is characterized by a striking degree of genetic and clinical heterogeneity. This heterogeneity poses a major barrier to understanding the genetic basis of the disease and its response to therapy. Here, we performed an integrative analysis of whole-exome sequencing and transcriptome sequencing in a cohort of 1,001 DLBCL patients to comprehensively define the landscape of 150 genetic drivers of the disease. We characterized the functional impact of these genes using an unbiased CRISPR screen of DLBCL cell lines to define oncogenes that promote cell growth. A prognostic model comprising these genetic alterations outperformed current established methods: cell of origin, the International Prognostic Index comprising clinical variables, and dual MYC and BCL2 expression. These results comprehensively define the genetic drivers and their functional roles in DLBCL to identify new therapeutic opportunities in the disease.

Publisher URL: http://www.cell.com/cell/fulltext/S0092-8674(17)31121-2

DOI: 10.1016/j.cell.2017.09.027

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