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Cell. 2017 Oct 5;171(2):481-494.e15. doi: 10.1016/j.cell.2017.09.027.

Genetic and Functional Drivers of Diffuse Large B Cell Lymphoma.

Author information

1
Duke Cancer Institute and Center for Genomic and Computational Biology, Duke University, Durham, NC, USA; Department of Medicine, Duke University Medical Center, Durham, NC, USA.
2
Duke Cancer Institute and Center for Genomic and Computational Biology, Duke University, Durham, NC, USA.
3
Helsinki University Hospital Cancer Center and University of Helsinki, Helsinki, Finland.
4
Herlev and Gentofte Hospital, Copenhagen University, Herlev, Denmark.
5
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA.
6
Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA.
7
Winship Cancer Institute, Emory University, Atlanta, GA, USA.
8
Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
9
Barts Cancer Institute of Queen Mary University of London, London, UK.
10
Pathology, Indiana University, Indianapolis, IN, USA.
11
Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH, USA.
12
Queen Mary Hospital, University of Hong Kong, Hong Kong.
13
Tufts University Medical Center, Boston, MA, USA.
14
Tata Memorial Center, Mumbai, India.
15
Vanderbilt University Medical Center, Nashville, TN, USA.
16
MD Anderson Cancer Center, Houston, TX, USA.
17
Columbia-Presbyterian Hospital, New York, NY, USA.
18
Northwestern University Medical School, Chicago, IL, USA.
19
National Cancer Institute, Bethesda, MD, USA.
20
Hudson Alpha Institute for Biotechnology, Huntsville, AL, USA.
21
Department of Statistical Science, Duke University, Durham, NC, USA.
22
Duke Cancer Institute and Center for Genomic and Computational Biology, Duke University, Durham, NC, USA; Department of Medicine, Duke University Medical Center, Durham, NC, USA. Electronic address: sandeep.dave@duke.edu.

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.

KEYWORDS:

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

PMID:
28985567
PMCID:
PMC5659841
DOI:
10.1016/j.cell.2017.09.027
[Indexed for MEDLINE]
Free PMC Article

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