Dataset Information

Genetic and Functional Drivers of Diffuse Large B Cell Lymphoma

ABSTRACT: Diffuse large B cell lymphoma (DLBCL) is the most common hematologic malignancy and is characterized by a striking degree of heterogeneity. We enrolled a total of 1001 DLBCL patients and comprehensively defined the landscape of genetic mutations, copy number alterations and expression through whole-exome and transcriptome sequencing. We identified 150 genetic drivers of DLBCL including many novel, clinically relevant genes (e.g. SPEN, SETD1B and KLHL14). Genetic drivers were highly enriched among essential genes identified by CRISPR screening in DLBCL cell lines including those of immediate potential therapeutic relevance such as MTOR, SYK, SF3B1 and XPO1. RHOA emerged as a critical driver gene from our genetic analysis and CRISPR screen; we further delineated its functional role in vitro and in vivo models to define its role as an essential oncogene in DLBCL. Our work thus identifies the functional landscape of genetic drivers and their clinical and therapeutic relevance in DLBCL patients.

PROVIDER: EGAS00001002606 | EGA |

REPOSITORIES: EGA

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Genetic and Functional Drivers of Diffuse Large B Cell Lymphoma.

Reddy Anupama A Zhang Jenny J Davis Nicholas S NS Moffitt Andrea B AB Love Cassandra L CL Waldrop Alexander A Leppa Sirpa S Pasanen Annika A Meriranta Leo L Karjalainen-Lindsberg Marja-Liisa ML Nørgaard Peter P Pedersen Mette M Gang Anne O AO Høgdall Estrid E Heavican Tayla B TB Lone Waseem W Iqbal Javeed J Qin Qiu Q Li Guojie G Kim So Young SY Healy Jane J Richards Kristy L KL Fedoriw Yuri Y Bernal-Mizrachi Leon L Koff Jean L JL Staton Ashley D AD Flowers Christopher R CR Paltiel Ora O Goldschmidt Neta N Calaminici Maria M Clear Andrew A Gribben John J Nguyen Evelyn E Czader Magdalena B MB Ondrejka Sarah L SL Collie Angela A Hsi Eric D ED Tse Eric E Au-Yeung Rex K H RKH Kwong Yok-Lam YL Srivastava Gopesh G Choi William W L WWL Evens Andrew M AM Pilichowska Monika M Sengar Manju M Reddy Nishitha N Li Shaoying S Chadburn Amy A Gordon Leo I LI Jaffe Elaine S ES Levy Shawn S Rempel Rachel R Tzeng Tiffany T Happ Lanie E LE Dave Tushar T Rajagopalan Deepthi D Datta Jyotishka J Dunson David B DB Dave Sandeep S SS

Cell 20171001 2

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 chara ...[more]

PMID: 28985567

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Project description:Analysis of the chronic lymphocytic leukemia coding genome: role of NOTCH1 mutational activation The pathogenesis of chronic lymphocytic leukemia (CLL), the most common leukemia in adults, is still largely unknown since the full spectrum of genetic lesions that are present in the CLL genome, and therefore the number and identity of dysregulated cellular pathways, have not been identified. By combining next-generation sequencing and copy number analysis, we show here that the typical CLL coding genome contains less than 20 clonally represented gene alterations/case, including predominantly non-silent mutations and fewer copy number aberrations. These analyses led to the discovery of several genes not previously known to be altered in CLL. While most of these genes were affected at low frequency in an expanded CLL screening cohort, mutational activation of NOTCH1, observed in 8.3% of CLL at diagnosis, was detected at significantly higher frequency during disease progression toward Richter transformation (31.0%) as well as in chemorefractory CLL (20.8%). Consistent with the association of NOTCH1 mutations with clinically aggressive forms of the disease, NOTCH1 activation at CLL diagnosis emerged as an independent predictor of poor survival. These results provide initial data on the complexity of the CLL coding genome and identify a dysregulated pathway of diagnostic and therapeutic relevance. Genetic Lesions associated with Chronic Lymphocytic Leukemia transformation to Richter Syndrome Richter syndrome (RS) derives from the rare transformation of chronic lymphocytic leukemia (CLL) into an aggressive lymphoma, most commonly of the diffuse large B cell type (DLBCL). The molecular pathogenesis of RS is only partially understood. By combining whole-exome sequencing and copy-number analysis of 9 CLL-RS pairs and of an extended panel of 43 RS cases, we show that this aggressive disease typically arises from the predominant CLL clone by acquiring an average of ~20 genetic lesions/case. RS lesions are heterogeneous in terms of load and spectrum among patients, and include those involved in CLL progression and chemorefractoriness (TP53 disruption and NOTCH1 activation) as well as some not previously implicated in CLL or RS pathogenesis. In particular, disruption of the CDKN2A/B cell cycle regulator locus is associated with ~30% of RS cases. Finally, we report that the genomic landscape of RS is significantly different from that of de novo DLBCL, suggesting that they represent distinct disease entities. These results provide insights into RS pathogenesis, and identify dysregulated pathways of potential diagnostic and therapeutic relevance.

Dataset Information

Genetic and Functional Drivers of Diffuse Large B Cell Lymphoma

Publications

Genetic and Functional Drivers of Diffuse Large B Cell Lymphoma.

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