Genetic heterogeneity of diffuse large B-cell lymphoma

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.next-generation sequencing | cancer genetics | cancer heterogeneity D iffuse large B-cell lymphoma (DLBCL) is the most common form of lymphoma in adults (1). Although nearly half the patients can be cured with standard regimens, the majority of relapsed patients succumb. Thus, there is an urgent need to identify the genetic underpinnings of the disease and to identify novel treatment strategies. Gene expression profiling (2, 3) has uncovered distinct molecular signatures for DLBCL subtypes that have unique biology and prognoses. High-throughput sequencing has provided rich opportunities for the comprehensive identification of the genetic causes of cancer (4-6). Whereas exhaustive portraits of individual cancer genomes are emerging, the degree to which these genomes represent the disease is unclear.We generated a detailed analysis of a DLBCL genome by sequencing a primary human tumor and paired normal tissue (Dataset S1). We further characterized the genetic diversity of DLBCL by sequencing the exomes of 73 DLBCL primary tumors (34 with matched normal DNA) and 21 DLBCL cell lines for comparative purposes. This in-depth sequencing identified 322 DLBCL cancer genes that were recurrently mutated in DLBCLs. We also experimentally validated the effects of genetic alteration of PIK3CD, an oncogene that we identified in DLBCL. Our work provides one of the largest genetic portraits yet of human DLBCLs and offers insights into the molecular heterogeneity of the disease, especially in the context of other recently published studies in DLBCL (7, 8).

Allogeneic hematopoietic cell transplantation for diffuse large B cell lymphoma: who, when and how?

“…Recent studies have identified significant molecular heterogeneity of DLBCL. 53 It will therefore ultimately be necessary to assay for several potential therapeutic targets in order to select the best regimen for an individual patient, ideally, in combination with either auto-HCT or allo-HCT, depending on the specific patient and disease characteristics. This would allow for 'individualized therapy' such that the proper 'targeted' agent can be matched to the appropriate tumor biology.…”

B-cell tumor development in Tet2-deficient mice

“…Intriguingly, although TET2 mutations are very rare in human CLL, 31 they are found in at least 5% of diffuse large B-cell lymphoma (DLBCL) samples. 10,11,32 Tet2-deficient tumors harbor AID-mediated somatic mutations…”

Whole-genome sequencing reveals oncogenic mutations in mycosis fungoides

“…18 High-throughput sequencing has identified novel genetic variants in many malignancies, including B-and T-cell lymphomas. 19,20 Because driver mutations in MF remain unidentified, we performed whole-genome sequencing (WGS) of MF tumor samples with matched normal skin controls, targeted deep sequencing of MF tumors, and exome sequencing of CTCL cell lines to identify mutations and altered pathways integral to MF development. Our results reveal mutations in cytokine and epigenetic regulation pathways that were common to MF tumors and CTCL lines, providing insight into MF.…”