Abstract
Burkitt lymphoma (BL) accounts for most pediatric non-Hodgkin lymphomas, being less common but significantly more lethal when diagnosed in adults. Much of the knowledge of the genetics of BL thus far has originated from the study of pediatric BL (pBL), leaving its relationship to adult BL (aBL) and other adult lymphomas not fully explored. We sought to more thoroughly identify the somatic changes that underlie lymphomagenesis in aBL and any molecular features that associate with clinical disparities within and between pBL and aBL. Through comprehensive whole-genome sequencing of 230 BL and 295 diffuse large B-cell lymphoma (DLBCL) tumors, we identified additional significantly mutated genes, including more genetic features that associate with tumor Epstein-Barr virus status, and unraveled new distinct subgroupings within BL and DLBCL with 3 predominantly comprising BLs: DGG-BL (DDX3X, GNA13, and GNAI2), IC-BL (ID3 and CCND3), and Q53-BL (quiet TP53). Each BL subgroup is characterized by combinations of common driver and noncoding mutations caused by aberrant somatic hypermutation. The largest subgroups of BL cases, IC-BL and DGG-BL, are further characterized by distinct biological and gene expression differences. IC-BL and DGG-BL and their prototypical genetic features (ID3 and TP53) had significant associations with patient outcomes that were different among aBL and pBL cohorts. These findings highlight shared pathogenesis between aBL and pBL, and establish genetic subtypes within BL that serve to delineate tumors with distinct molecular features, providing a new framework for epidemiologic, diagnostic, and therapeutic strategies.
| Original language | English |
|---|---|
| Pages (from-to) | 904-916 |
| Number of pages | 13 |
| Journal | Blood |
| Volume | 141 |
| Issue number | 8 |
| DOIs | |
| State | Published - Feb 23 2023 |
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In: Blood, Vol. 141, No. 8, 23.02.2023, p. 904-916.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Genetic subgroups inform on pathobiology in adult and pediatric Burkitt lymphoma
AU - Thomas, Nicole
AU - Dreval, Kostiantyn
AU - Gerhard, Daniela S.
AU - Hilton, Laura K.
AU - Abramson, Jeremy S.
AU - Ambinder, Richard F.
AU - Barta, Stefan
AU - Bartlett, Nancy L.
AU - Bethony, Jeffrey
AU - Bhatia, Kishor
AU - Bowen, Jay
AU - Bryan, Anthony C.
AU - Cesarman, Ethel
AU - Casper, Corey
AU - Chadburn, Amy
AU - Cruz, Manuela
AU - Dittmer, Dirk P.
AU - Dyer, Maureen A.
AU - Farinha, Pedro
AU - Gastier-Foster, Julie M.
AU - Gerrie, Alina S.
AU - Grande, Bruno M.
AU - Greiner, Timothy
AU - Griner, Nicholas B.
AU - Gross, Thomas G.
AU - Harris, Nancy L.
AU - Irvin, John D.
AU - Jaffe, Elaine S.
AU - Henry, David
AU - Huppi, Rebecca
AU - Leal, Fabio E.
AU - Lee, Michael S.
AU - Martin, Jean Paul
AU - Martin, Marie Reine
AU - Mbulaiteye, Sam M.
AU - Mitsuyasu, Ronald
AU - Morris, Vivian
AU - Mullighan, Charles G.
AU - Mungall, Andrew J.
AU - Mungall, Karen
AU - Mutyaba, Innocent
AU - Nokta, Mostafa
AU - Namirembe, Constance
AU - Noy, Ariela
AU - Ogwang, Martin D.
AU - Omoding, Abraham
AU - Orem, Jackson
AU - Ott, German
AU - Petrello, Hilary
AU - Pittaluga, Stefania
AU - Phelan, James D.
AU - Ramos, Juan Carlos
AU - Ratner, Lee
AU - Reynolds, Steven J.
AU - Rubinstein, Paul G.
AU - Sissolak, Gerhard
AU - Slack, Graham
AU - Soudi, Shaghayegh
AU - Swerdlow, Steven H.
AU - Traverse-Glehen, Alexandra
AU - Wilson, Wyndham H.
AU - Wong, Jasper
AU - Yarchoan, Robert
AU - ZenKlusen, Jean C.
AU - Marra, Marco A.
AU - Staudt, Louis M.
AU - Scott, David W.
AU - Morin, Ryan D.
N1 - Funding Information: This work has been funded in part by the Foundation for Burkitt Lymphoma Research ( http://www.foundationforburkittlymphoma.org ) and in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health (NIH), under contract no. 75N91019D00024, task order no. 75N91020F00003, contract no. HHSN261200800001E, contract no. HHSN261201100063C, and contract no. HHSN261201100007I (Division of Cancer Epidemiology and Genetics), and in part (S.J.R.) by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH. This project was also partially supported by AIDS Malignancy Consortium grant UM1CA121947 and the Intramural Research Program of the NIH, National Cancer Institute . The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government. This work was supported by a Terry Fox New Investigator Award (No. 1043) and by an operating grant from the Canadian Institutes for Health Research and a New Investigator Award from the Canadian Institutes for Health Research (R.D.M.). R.D.M. is a Michael Smith Foundation for Health Research Scholar, and D.W.S. is a Michael Smith Foundation for Health Research Health Professional-Investigator. M.A.M. is the recipient of the Canada Research Chair in Genome Science. Funding Information: The authors thank the Foundation for Burkitt Lymphoma Research Working Group for interesting discussions. The authors also acknowledge the Information Management Systems (Silver Spring, MD), Westat, Inc (Rockville, MD), and African Field Epidemiology Network (Kampala, Uganda) for coordinating The Epidemiology of Burkitt lymphoma in East African children and minors (EMBLEM) fieldwork in Uganda. The authors also acknowledge the International Cancer Genome Consortium Molecular Mechanisms in Malignant Lymphoma by Sequencing project ( https://dcc.icgc.org ) for providing access to its data. Aligned reads for those genomes were obtained through a Data Access Compliance Office-approved project (to R.D.M.) using a virtual instance on the Cancer Genome Collaboratory. The data sets for validation cohorts were obtained through The European Genome-phenome Archive (data set identifiers EGAD00001005105 and EGAD00001005781) on Data Access Committee approval. The Genomic Variation in Diffuse Large B Cell Lymphomas study was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health (NIH), Department of Health and Human Services . The data sets have been accessed through the NIH database for Genotypes and Phenotypes. A full list of acknowledgments can be found in the supplemental note (Schmitz et al, PMID: 29641966 ). 26 The authors also thank the HIV Tumor Malignancy Characterization Network and the AIDS and Cancer Specimen Resource for their valuable contribution of samples to this study. The authors are grateful for contributions from various groups at Canada’s Michael Smith Genome Sciences Centre, including those from the Biospecimen, Library Construction, Sequencing, Bioinformatics, Technology Development, Quality Assurance, Laboratory Information Management System, Purchasing, and Project Management teams. The authors also thank The Biorepository of St. Jude Children’s Research Hospital (National Cancer Institute grants P30 CA021765 and R35 CA197695 to C.G.M.). Funding Information: The authors thank the Foundation for Burkitt Lymphoma Research Working Group for interesting discussions. The authors also acknowledge the Information Management Systems (Silver Spring, MD), Westat, Inc (Rockville, MD), and African Field Epidemiology Network (Kampala, Uganda) for coordinating The Epidemiology of Burkitt lymphoma in East African children and minors (EMBLEM) fieldwork in Uganda. The authors also acknowledge the International Cancer Genome Consortium Molecular Mechanisms in Malignant Lymphoma by Sequencing project (https://dcc.icgc.org) for providing access to its data. Aligned reads for those genomes were obtained through a Data Access Compliance Office-approved project (to R.D.M.) using a virtual instance on the Cancer Genome Collaboratory. The data sets for validation cohorts were obtained through The European Genome-phenome Archive (data set identifiers EGAD00001005105 and EGAD00001005781) on Data Access Committee approval. The Genomic Variation in Diffuse Large B Cell Lymphomas study was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health (NIH), Department of Health and Human Services. The data sets have been accessed through the NIH database for Genotypes and Phenotypes. A full list of acknowledgments can be found in the supplemental note (Schmitz et al, PMID: 29641966).26 The authors also thank the HIV Tumor Malignancy Characterization Network and the AIDS and Cancer Specimen Resource for their valuable contribution of samples to this study. The authors are grateful for contributions from various groups at Canada's Michael Smith Genome Sciences Centre, including those from the Biospecimen, Library Construction, Sequencing, Bioinformatics, Technology Development, Quality Assurance, Laboratory Information Management System, Purchasing, and Project Management teams. The authors also thank The Biorepository of St. Jude Children's Research Hospital (National Cancer Institute grants P30 CA021765 and R35 CA197695 to C.G.M.). This work has been funded in part by the Foundation for Burkitt Lymphoma Research (http://www.foundationforburkittlymphoma.org) and in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health (NIH), under contract no. 75N91019D00024, task order no. 75N91020F00003, contract no. HHSN261200800001E, contract no. HHSN261201100063C, and contract no. HHSN261201100007I (Division of Cancer Epidemiology and Genetics), and in part (S.J.R.) by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH. This project was also partially supported by AIDS Malignancy Consortium grant UM1CA121947 and the Intramural Research Program of the NIH, National Cancer Institute. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government. This work was supported by a Terry Fox New Investigator Award (No. 1043) and by an operating grant from the Canadian Institutes for Health Research and a New Investigator Award from the Canadian Institutes for Health Research (R.D.M.). R.D.M. is a Michael Smith Foundation for Health Research Scholar, and D.W.S. is a Michael Smith Foundation for Health Research Health Professional-Investigator. M.A.M. is the recipient of the Canada Research Chair in Genome Science. This article is dedicated to the memory of Daniela S. Gerhard. Contribution: N.T. and K.D. analyzed the data, produced the figures and tables, and with R.D.M. wrote the manuscript with assistance from D.S.G. J. Bethony, C.C. T.G. N.L.H. E.S.J. S.M.M. C.G.M. A.J.M. A.N. M.A.M. and D.W.S.; B.M.G. L.K.H. M.C. S.S. and J.W. helped with data analyses; D.S.G. M.A.D. N.B.G. and H.P. managed the project and coordinated data deposition; J.S.A. J. Bowen, C.C. J.M.G.-F. T.G.G. F.E.L. S.M.M. C.G.M. C.N. A.N. M.D.O. J.O. G.O. S.J.R. D.W.S. R.Y. R.H. M.N. K.B. A.O. I.M. L.R. D.H. R.M. J.C.R. P.G.R. M.S.L. S.B. E.C. S.S. G. Sissolak, S.P. R.F.A. A.C. D.P.D. and J.C.Z. contributed samples to the study; J. Bowen, J.M.G.-F. and A.S.G. collected sample metadata from tissue source sites; T.G. N.L.H. E.S.J. and S.H.S. performed consensus pathology review; C.C. T.G.G. and E.S.J. reviewed and advised on consensus anatomic site classification; D.S.G. J.D.I. J.P.M. M.-R.M. R.D.M. and L.M.S. designed the study; D.S.G. M.A.M. R.D.M. and L.M.S. directed the study; and all authors contributed to the interpretation of the data, reviewed the manuscript, and approved it for submission. Publisher Copyright: © 2023
PY - 2023/2/23
Y1 - 2023/2/23
N2 - Burkitt lymphoma (BL) accounts for most pediatric non-Hodgkin lymphomas, being less common but significantly more lethal when diagnosed in adults. Much of the knowledge of the genetics of BL thus far has originated from the study of pediatric BL (pBL), leaving its relationship to adult BL (aBL) and other adult lymphomas not fully explored. We sought to more thoroughly identify the somatic changes that underlie lymphomagenesis in aBL and any molecular features that associate with clinical disparities within and between pBL and aBL. Through comprehensive whole-genome sequencing of 230 BL and 295 diffuse large B-cell lymphoma (DLBCL) tumors, we identified additional significantly mutated genes, including more genetic features that associate with tumor Epstein-Barr virus status, and unraveled new distinct subgroupings within BL and DLBCL with 3 predominantly comprising BLs: DGG-BL (DDX3X, GNA13, and GNAI2), IC-BL (ID3 and CCND3), and Q53-BL (quiet TP53). Each BL subgroup is characterized by combinations of common driver and noncoding mutations caused by aberrant somatic hypermutation. The largest subgroups of BL cases, IC-BL and DGG-BL, are further characterized by distinct biological and gene expression differences. IC-BL and DGG-BL and their prototypical genetic features (ID3 and TP53) had significant associations with patient outcomes that were different among aBL and pBL cohorts. These findings highlight shared pathogenesis between aBL and pBL, and establish genetic subtypes within BL that serve to delineate tumors with distinct molecular features, providing a new framework for epidemiologic, diagnostic, and therapeutic strategies.
AB - Burkitt lymphoma (BL) accounts for most pediatric non-Hodgkin lymphomas, being less common but significantly more lethal when diagnosed in adults. Much of the knowledge of the genetics of BL thus far has originated from the study of pediatric BL (pBL), leaving its relationship to adult BL (aBL) and other adult lymphomas not fully explored. We sought to more thoroughly identify the somatic changes that underlie lymphomagenesis in aBL and any molecular features that associate with clinical disparities within and between pBL and aBL. Through comprehensive whole-genome sequencing of 230 BL and 295 diffuse large B-cell lymphoma (DLBCL) tumors, we identified additional significantly mutated genes, including more genetic features that associate with tumor Epstein-Barr virus status, and unraveled new distinct subgroupings within BL and DLBCL with 3 predominantly comprising BLs: DGG-BL (DDX3X, GNA13, and GNAI2), IC-BL (ID3 and CCND3), and Q53-BL (quiet TP53). Each BL subgroup is characterized by combinations of common driver and noncoding mutations caused by aberrant somatic hypermutation. The largest subgroups of BL cases, IC-BL and DGG-BL, are further characterized by distinct biological and gene expression differences. IC-BL and DGG-BL and their prototypical genetic features (ID3 and TP53) had significant associations with patient outcomes that were different among aBL and pBL cohorts. These findings highlight shared pathogenesis between aBL and pBL, and establish genetic subtypes within BL that serve to delineate tumors with distinct molecular features, providing a new framework for epidemiologic, diagnostic, and therapeutic strategies.
UR - http://www.scopus.com/inward/record.url?scp=85144933575&partnerID=8YFLogxK
U2 - 10.1182/blood.2022016534
DO - 10.1182/blood.2022016534
M3 - Article
C2 - 36201743
AN - SCOPUS:85144933575
SN - 0006-4971
VL - 141
SP - 904
EP - 916
JO - Blood
JF - Blood
IS - 8
ER -