Title | Genetic heterogeneity of diffuse large B-cell lymphoma. |
Publication Type | Journal Article |
Year of Publication | 2013 |
Authors | Zhang J, Grubor V, Love CL, Banerjee A, Richards KL, Mieczkowski PA, Dunphy C, Choi W, Au WYan, 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 |
Journal | Proc Natl Acad Sci U S A |
Volume | 110 |
Issue | 4 |
Pagination | 1398-403 |
Date Published | 2013 Jan 22 |
ISSN | 1091-6490 |
Keywords | 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 |
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. |
DOI | 10.1073/pnas.1205299110 |
Alternate Journal | Proc Natl Acad Sci U S A |
PubMed ID | 23292937 |
PubMed Central ID | PMC3557051 |
Grant List | R01 CA140337 / CA / NCI NIH HHS / United States R21CA1561686 / CA / NCI NIH HHS / United States R01 CA136895 / CA / NCI NIH HHS / United States R01 ES017436 / ES / NIEHS NIH HHS / United States R01CA136895 / CA / NCI NIH HHS / United States P30 AI064518 / AI / NIAID NIH HHS / United States |
Related Faculty:
Amy Chadburn, M.D.