Genetic and Functional Drivers of Diffuse Large B Cell Lymphoma

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.

Type: Other
Archiver: European Genome-Phenome Archive (EGA)

1 Dataset 24 Publications

Click on a Dataset ID in the table below to learn more, and to find out who to contact about access to these data

Dataset ID	Description	Technology	Samples
EGAD00001003600	Exome sequencing data for 1001 DLBCL patients and RNA sequencing data for 775 DLBCL patients	Illumina HiSeq 2500	1776

Publications	Citations
Genetic and Functional Drivers of Diffuse Large B Cell Lymphoma. Reddy A, Zhang J, Davis NS, Moffitt AB, Love CL, Waldrop A, Leppa S, Pasanen A, Meriranta L, Karjalainen-Lindsberg ML, Nørgaard P, Pedersen M, Gang AO, Høgdall E, Heavican TB, Lone W, Iqbal J, Qin Q, Li G, Kim SY, Healy J, Richards KL, Fedoriw Y, Bernal-Mizrachi L, Koff JL, Staton AD, Flowers CR, Paltiel O, Goldschmidt N, Calaminici M, Clear A, Gribben J, Nguyen E, Czader MB, Ondrejka SL, Collie A, Hsi ED, Tse E, Au-Yeung RKH, Kwong YL, Srivastava G, Choi WWL, Evens AM, Pilichowska M, Sengar M, Reddy N, Li S, Chadburn A, Gordon LI, Jaffe ES, Levy S, Rempel R, Tzeng T, Happ LE, Dave T, Rajagopalan D, Datta J, Dunson DB, Dave SS. Cell 171: 2017 481-494.e15	584
B cells with aberrant activation of Notch1 signaling promote Treg and Th2 cell-dominant T-cell responses via IL-33. Arima H, Nishikori M, Otsuka Y, Kishimoto W, Izumi K, Yasuda K, Yoshimoto T, Takaori-Kondo A. Blood Adv 2: 2018 2282-2295	14
Genome-wide discovery of somatic regulatory variants in diffuse large B-cell lymphoma. Arthur SE, Jiang A, Grande BM, Alcaide M, Cojocaru R, Rushton CK, Mottok A, Hilton LK, Lat PK, Zhao EY, Culibrk L, Ennishi D, Jessa S, Chong L, Thomas N, Pararajalingam P, Meissner B, Boyle M, Davidson J, Bushell KR, Lai D, Farinha P, Slack GW, Morin GB, Shah S, Sen D, Jones SJM, Mungall AJ, Gascoyne RD, Audas TE, Unrau P, Marra MA, Connors JM, Steidl C, Scott DW, Morin RD. Nat Commun 9: 2018 4001	86
Molecular High-Grade B-Cell Lymphoma: Defining a Poor-Risk Group That Requires Different Approaches to Therapy. Sha C, Barrans S, Cucco F, Bentley MA, Care MA, Cummin T, Kennedy H, Thompson JS, Uddin R, Worrillow L, Chalkley R, van Hoppe M, Ahmed S, Maishman T, Caddy J, Schuh A, Mamot C, Burton C, Tooze R, Davies A, Du MQ, Johnson PWM, Westhead DR. J Clin Oncol 37: 2019 202-212	134
The Identification and Interpretation of cis-Regulatory Noncoding Mutations in Cancer. Patel MB, Wang J. High Throughput 8: 2018 E1	4
Genome-defined African ancestry is associated with distinct mutations and worse survival in patients with diffuse large B-cell lymphoma. Lee MJ, Koff JL, Switchenko JM, Jhaney CI, Harkins RA, Patel SP, Dave SS, Flowers CR. Cancer 126: 2020 3493-3503	12
Optimized Doxorubicin Chemotherapy for Diffuse Large B-cell Lymphoma Exploits Nanocarrier Delivery to Transferrin Receptors. Arumov A, Liyanage PY, Trabolsi A, Roberts ER, Li L, Ferreira BCLB, Gao Z, Ban Y, Newsam AD, Taggart MW, Vega F, Bilbao D, Leblanc RM, Schatz JH. Cancer Res 81: 2021 763-775	9
PRPS-ST: A protocol-agnostic self-training method for gene expression-based classification of blood cancers. Jiang A, Hilton LK, Tang J, Tang J, Rushton CK, Grande BM, Scott DW, Morin RD. Blood Cancer Discov 1: 2020 244-257	2
An Autochthonous Mouse Model of Myd88- and BCL2-Driven Diffuse Large B-cell Lymphoma Reveals Actionable Molecular Vulnerabilities. Flümann R, Rehkämper T, Nieper P, Pfeiffer P, Holzem A, Klein S, Bhatia S, Kochanek M, Kisis I, Pelzer BW, Ahlert H, Hauer J, da Palma Guerreiro A, Ryan JA, Reimann M, Riabinska A, Wiederstein J, Krüger M, Deckert M, Altmüller J, Klatt AR, Frenzel LP, Pasqualucci L, Béguelin W, Melnick AM, Sander S, Montesinos-Rongen M, Brunn A, Lohneis P, Büttner R, Kashkar H, Borkhardt A, Letai A, Persigehl T, Peifer M, Schmitt CA, Reinhardt HC, Knittel G. Blood Cancer Discov 2: 2021 70-91	22
The landscape of tumor cell states and ecosystems in diffuse large B cell lymphoma. Steen CB, Luca BA, Esfahani MS, Azizi A, Sworder BJ, Nabet BY, Kurtz DM, Liu CL, Khameneh F, Advani RH, Natkunam Y, Myklebust JH, Diehn M, Gentles AJ, Newman AM, Alizadeh AA. Cancer Cell 39: 2021 1422-1437.e10	99
Targeting mitochondrial respiration and the BCL2 family in high-grade MYC-associated B-cell lymphoma. Donati G, Ravà M, Filipuzzi M, Nicoli P, Cassina L, Verrecchia A, Doni M, Rodighiero S, Parodi F, Boletta A, Vellano CP, Marszalek JR, Draetta GF, Amati B. Mol Oncol 16: 2022 1132-1152	6
Clinical Impact of Immune Cells and Their Spatial Interactions in Diffuse Large B-Cell Lymphoma Microenvironment. Autio M, Leivonen SK, Brück O, Karjalainen-Lindsberg ML, Pellinen T, Leppä S. Clin Cancer Res 28: 2022 781-792	19
Disrupting the MYC-TFEB Circuit Impairs Amino Acid Homeostasis and Provokes Metabolic Anergy. Fernandez MR, Schaub FX, Yang C, Li W, Yun S, Schaub SK, Dorsey FC, Liu M, Steeves MA, Ballabio A, Tzankov A, Chen Z, Koomen JM, Berglund AE, Cleveland JL. Cancer Res 82: 2022 1234-1250	6
PIM1 genetic alterations associated with distinct molecular profiles, phenotypes and drug responses in diffuse large B-cell lymphoma. Zhang H, Lu Y, Zhang T, Guan Q, Wang X, Guo Y, Li L, Qiu L, Qian Z, Zhou S, Gong W, Meng B, Ren X, Wang X. Clin Transl Med 12: 2022 e808	7
Tumoral microenvironment prevents de novo asparagine biosynthesis in B cell lymphoma, regardless of ASNS expression. Grima-Reyes M, Vandenberghe A, Nemazanyy I, Meola P, Paul R, Reverso-Meinietti J, Martinez-Turtos A, Nottet N, Chan WK, Lorenzi PL, Marchetti S, Ricci JE, Chiche J. Sci Adv 8: 2022 eabn6491	7
TCR-Independent Metabolic Reprogramming Precedes Lymphoma-Driven Changes in T-cell Fate. Hesterberg RS, Liu M, Elmarsafawi AG, Koomen JM, Welsh EA, Hesterberg SG, Ranatunga S, Yang C, Li W, Lawrence HR, Rodriguez PC, Berglund AE, Cleveland JL. Cancer Immunol Res 10: 2022 1263-1279	1
Minimal information for reporting a genomics experiment. Dreval K, Boutros PC, Morin RD. Blood 140: 2022 2549-2555	2
Sex- and Female Age-Dependent Differences in Gene Expression in Diffuse Large B-Cell Lymphoma-Possible Estrogen Effects. Huang D, Berglund M, Damdimopoulos A, Antonson P, Lindskog C, Enblad G, Amini RM, Okret S. Cancers (Basel) 15: 2023 1298	2
Combinatorial treatment rescues tumour-microenvironment-mediated attenuation of MALT1 inhibitors in B-cell lymphomas. Shah SB, Carlson CR, Lai K, Zhong Z, Marsico G, Lee KM, Félix Vélez NE, Abeles EB, Allam M, Hu T, Walter LD, Martin KE, Gandhi K, Butler SD, Puri R, McCleary-Wheeler AL, Tam W, Elemento O, Takata K, Steidl C, Scott DW, Fontan L, Ueno H, Cosgrove BD, Inghirami G, García AJ, Coskun AF, Koff JL, Melnick A, Singh A. Nat Mater 22: 2023 511-523	20
Patterns of Oncogene Coexpression at Single-Cell Resolution Influence Survival in Lymphoma. Hoppe MM, Jaynes P, Shuangyi F, Peng Y, Sridhar S, Hoang PM, Liu CX, De Mel S, Poon L, Chan EHL, Lee J, Ong CK, Tang T, Lim ST, Nagarajan C, Grigoropoulos NF, Tan SY, Hue SS, Chang ST, Chuang SS, Li S, Khoury JD, Choi H, Harris C, Bottos A, Gay LJ, Runge HFP, Moutsopoulos I, Mohorianu I, Hodson DJ, Farinha P, Mottok A, Scott DW, Pitt JJ, Chen J, Kumar G, Kannan K, Chng WJ, Chee YL, Ng SB, Tripodo C, Jeyasekharan AD. Cancer Discov 13: 2023 1144-1163	2
The Oncogenic Lipid Sphingosine-1-Phosphate Impedes the Phagocytosis of Tumor Cells by M1 Macrophages in Diffuse Large B Cell Lymphoma. Perry TA, Masand N, Vrzalikova K, Pugh M, Wei W, Hollows R, Bouchalova K, Nohtani M, Fennell E, Bouchal J, Kearns P, Murray PG. Cancers (Basel) 16: 2024 574	0
A Cluster of Evolutionarily Recent KRAB Zinc Finger Proteins Protects Cancer Cells from Replicative Stress-Induced Inflammation. Martins F, Martins F, Rosspopoff O, Carlevaro-Fita J, Forey R, Offner S, Planet E, Pulver C, Pak H, Huber F, Michaux J, Bassani-Sternberg M, Turelli P, Trono D. Cancer Res 84: 2024 808-826	1
Spatially-resolved transcriptomics reveal macrophage heterogeneity and prognostic significance in diffuse large B-cell lymphoma. Liu M, Bertolazzi G, Sridhar S, Lee RX, Jaynes P, Mulder K, Syn N, Hoppe MM, Fan S, Peng Y, Thng J, Chua R, Jayalakshmi, Batumalai Y, De Mel S, Poon L, Chan EHL, Lee J, Hue SS, Chang ST, Chuang SS, Chandy KG, Ye X, Pan-Hammarström Q, Ginhoux F, Chee YL, Ng SB, Tripodo C, Jeyasekharan AD. Nat Commun 15: 2024 2113	3
Multiomic analysis identifies a high-risk signature that predicts early clinical failure in DLBCL. Wenzl K, Stokes ME, Novak JP, Bock AM, Khan S, Hopper MA, Krull JE, Dropik AR, Walker JS, Sarangi V, Mwangi R, Ortiz M, Stong N, Huang CC, Maurer MJ, Rimsza L, Link BK, Slager SL, Asmann Y, Mondello P, Morin R, Ansell SM, Habermann TM, Witzig TE, Feldman AL, King RL, Nowakowski G, Cerhan JR, Gandhi AK, Novak AJ. Blood Cancer J 14: 2024 100	2