Genetic and Functional Drivers of Diffuse Large B Cell Lymphoma

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

Research output: Contribution to journalArticle

162 Citations (Scopus)

Abstract

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. An integrative analysis in 1,001 newly diagnosed DLBCL patients identifies 150 genetic drivers with functional characterization using an unbiased CRISPR screen in DLBCL cell lines and connects with clinical outcome.

Original languageEnglish (US)
Pages (from-to)481-494.e15
JournalCell
Volume171
Issue number2
DOIs
StatePublished - Oct 5 2017

Fingerprint

Lymphoma, Large B-Cell, Diffuse
Clustered Regularly Interspaced Short Palindromic Repeats
Cells
Inborn Genetic Diseases
Cell growth
Blood
Genes
Exome
Cell Line
Genetic Heterogeneity
Genetic Models
Oncogenes
Transcriptome
Therapeutics
Growth
Neoplasms

Keywords

  • DLBCL
  • TCGA
  • The Cancer Genome Atlas
  • diffuse large B cell lymphoma
  • exome sequencing
  • genetic mutations

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Reddy, A., Zhang, J., Davis, N. S., Moffitt, A. B., Love, C. L., Waldrop, A., ... Dave, S. S. (2017). Genetic and Functional Drivers of Diffuse Large B Cell Lymphoma. Cell, 171(2), 481-494.e15. https://doi.org/10.1016/j.cell.2017.09.027

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

In: Cell, Vol. 171, No. 2, 05.10.2017, p. 481-494.e15.

Research output: Contribution to journalArticle

Reddy, A, Zhang, J, Davis, NS, Moffitt, AB, Love, CL, Waldrop, A, Leppa, S, Pasanen, A, Meriranta, L, Karjalainen-Lindsberg, ML, Nørgaard, P, Pedersen, M, Gang, AO, Høgdall, E, Heavican, TB, Lone, W, Iqbal, J, Qin, Q, Li, G, Kim, SY, Healy, J, Richards, KL, Fedoriw, Y, Bernal-Mizrachi, L, Koff, JL, Staton, AD, Flowers, CR, Paltiel, O, Goldschmidt, N, Calaminici, M, Clear, A, Gribben, J, Nguyen, E, Czader, MB, Ondrejka, SL, Collie, A, Hsi, ED, Tse, E, Au-Yeung, RKH, Kwong, YL, Srivastava, G, Choi, WWL, Evens, AM, Pilichowska, M, Sengar, M, Reddy, N, Li, S, Chadburn, A, Gordon, LI, Jaffe, ES, Levy, S, Rempel, R, Tzeng, T, Happ, LE, Dave, T, Rajagopalan, D, Datta, J, Dunson, DB & Dave, SS 2017, 'Genetic and Functional Drivers of Diffuse Large B Cell Lymphoma', Cell, vol. 171, no. 2, pp. 481-494.e15. https://doi.org/10.1016/j.cell.2017.09.027
Reddy A, Zhang J, Davis NS, Moffitt AB, Love CL, Waldrop A et al. Genetic and Functional Drivers of Diffuse Large B Cell Lymphoma. Cell. 2017 Oct 5;171(2):481-494.e15. https://doi.org/10.1016/j.cell.2017.09.027
Reddy, Anupama ; Zhang, Jenny ; Davis, Nicholas S. ; Moffitt, Andrea B. ; Love, Cassandra L. ; Waldrop, Alexander ; Leppa, Sirpa ; Pasanen, Annika ; Meriranta, Leo ; Karjalainen-Lindsberg, Marja Liisa ; Nørgaard, Peter ; Pedersen, Mette ; Gang, Anne O. ; Høgdall, Estrid ; Heavican, Tayla B. ; Lone, Waseem ; Iqbal, Javeed ; Qin, Qiu ; Li, Guojie ; Kim, So Young ; Healy, Jane ; Richards, Kristy L. ; Fedoriw, Yuri ; Bernal-Mizrachi, Leon ; Koff, Jean L. ; Staton, Ashley D. ; Flowers, Christopher R. ; Paltiel, Ora ; Goldschmidt, Neta ; Calaminici, Maria ; Clear, Andrew ; Gribben, John ; Nguyen, Evelyn ; Czader, Magdalena B. ; Ondrejka, Sarah L. ; Collie, Angela ; Hsi, Eric D. ; Tse, Eric ; Au-Yeung, Rex K.H. ; Kwong, Yok Lam ; Srivastava, Gopesh ; Choi, William W.L. ; Evens, Andrew M. ; Pilichowska, Monika ; Sengar, Manju ; Reddy, Nishitha ; Li, Shaoying ; Chadburn, Amy ; Gordon, Leo I. ; Jaffe, Elaine S. ; Levy, Shawn ; Rempel, Rachel ; Tzeng, Tiffany ; Happ, Lanie E. ; Dave, Tushar ; Rajagopalan, Deepthi ; Datta, Jyotishka ; Dunson, David B. ; Dave, Sandeep S. / Genetic and Functional Drivers of Diffuse Large B Cell Lymphoma. In: Cell. 2017 ; Vol. 171, No. 2. pp. 481-494.e15.
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AU - Srivastava, Gopesh

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