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Genetic heterogeneity of diffuse large B-cell lymphoma. Proc Natl Acad Sci U S A 2013 Jan 22;110(4):1398-403

Date

01/08/2013

Pubmed ID

23292937

Pubmed Central ID

PMC3557051

DOI

10.1073/pnas.1205299110

Scopus ID

2-s2.0-84872856782 (requires institutional sign-in at Scopus site)   462 Citations

Abstract

Diffuse large B-cell lymphoma (DLBCL) is the most common form of lymphoma in adults. The disease exhibits a striking heterogeneity in gene expression profiles and clinical outcomes, but its genetic causes remain to be fully defined. Through whole genome and exome sequencing, we characterized the genetic diversity of DLBCL. In all, we sequenced 73 DLBCL primary tumors (34 with matched normal DNA). Separately, we sequenced the exomes of 21 DLBCL cell lines. We identified 322 DLBCL cancer genes that were recurrently mutated in primary DLBCLs. We identified recurrent mutations implicating a number of known and not previously identified genes and pathways in DLBCL including those related to chromatin modification (ARID1A and MEF2B), NF-κB (CARD11 and TNFAIP3), PI3 kinase (PIK3CD, PIK3R1, and MTOR), B-cell lineage (IRF8, POU2F2, and GNA13), and WNT signaling (WIF1). We also experimentally validated a mutation in PIK3CD, a gene not previously implicated in lymphomas. The patterns of mutation demonstrated a classic long tail distribution with substantial variation of mutated genes from patient to patient and also between published studies. Thus, our study reveals the tremendous genetic heterogeneity that underlies lymphomas and highlights the need for personalized medicine approaches to treating these patients.

Author List

Zhang J, Grubor V, Love CL, Banerjee A, Richards KL, Mieczkowski PA, Dunphy C, Choi W, Au WY, Srivastava G, Lugar PL, Rizzieri DA, Lagoo AS, Bernal-Mizrachi L, Mann KP, Flowers C, Naresh K, Evens A, Gordon LI, Czader M, Gill JI, Hsi ED, Liu Q, Fan A, Walsh K, Jima D, Smith LL, Johnson AJ, Byrd JC, Luftig MA, Ni T, Zhu J, Chadburn A, Levy S, Dunson D, Dave SS

Author

Anjishnu Banerjee PhD Associate Professor in the Data Science Institute department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Adult
Base Sequence
Cell Line, Tumor
Class I Phosphatidylinositol 3-Kinases
DNA Mutational Analysis
DNA, Neoplasm
Exome
Gene Expression
Genetic Heterogeneity
Genetic Variation
Humans
Lymphoma, Large B-Cell, Diffuse
Models, Molecular
Molecular Sequence Data
Molecular Targeted Therapy
Mutation
Oncogenes
Phosphatidylinositol 3-Kinases
Protein Conformation
Proto-Oncogene Proteins c-kit
Receptor, Platelet-Derived Growth Factor alpha
Sequence Homology, Nucleic Acid
Signal Transduction