Genetic subgroups inform on pathobiology in adult and pediatric Burkitt lymphoma

Author:

Thomas Nicole1,Dreval Kostiantyn1,Gerhard Daniela S.2,Hilton Laura K.3ORCID,Abramson Jeremy S.4ORCID,Ambinder Richard F.5,Barta Stefan6,Bartlett Nancy L.7ORCID,Bethony Jeffrey8,Bhatia Kishor9,Bowen Jay10ORCID,Bryan Anthony C.10,Cesarman Ethel11ORCID,Casper Corey12ORCID,Chadburn Amy13,Cruz Manuela1,Dittmer Dirk P.14,Dyer Maureen A.15,Farinha Pedro3ORCID,Gastier-Foster Julie M.1016,Gerrie Alina S.3ORCID,Grande Bruno M.17ORCID,Greiner Timothy18ORCID,Griner Nicholas B.2,Gross Thomas G.19,Harris Nancy L.20,Irvin John D.21,Jaffe Elaine S.22ORCID,Henry David6,Huppi Rebecca23,Leal Fabio E.24,Lee Michael S.25,Martin Jean Paul21,Martin Marie-Reine21,Mbulaiteye Sam M.26ORCID,Mitsuyasu Ronald27,Morris Vivian28,Mullighan Charles G.29ORCID,Mungall Andrew J.30ORCID,Mungall Karen30,Mutyaba Innocent31,Nokta Mostafa23,Namirembe Constance31,Noy Ariela32ORCID,Ogwang Martin D.33,Omoding Abraham31,Orem Jackson31ORCID,Ott German34,Petrello Hilary10,Pittaluga Stefania22ORCID,Phelan James D.28,Ramos Juan Carlos35,Ratner Lee7,Reynolds Steven J.36,Rubinstein Paul G.37ORCID,Sissolak Gerhard38,Slack Graham3,Soudi Shaghayegh1,Swerdlow Steven H.39ORCID,Traverse-Glehen Alexandra40,Wilson Wyndham H.28,Wong Jasper3ORCID,Yarchoan Robert23ORCID,ZenKlusen Jean C.41,Marra Marco A.3042ORCID,Staudt Louis M.28,Scott David W.3ORCID,Morin Ryan D.1330ORCID

Affiliation:

1. 1Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada

2. 2Office of Cancer Genomics, National Cancer Institute, National Institutes of Health, Bethesda, MD

3. 3Centre for Lymphoid Cancer, BC Cancer, Vancouver, BC, Canada

4. 4Center for Lymphoma, Massachusetts General Hospital, Harvard Medical School, Boston, MA

5. 5Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD

6. 6University of Pennsylvania Hospital, Philadelphia, PA

7. 7Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO

8. 8Department of Microbiology, Immunology, and Tropical Medicine, George Washington University, Washington, DC

9. 9Lantern Pharma, Inc, Dallas, TX

10. 10Biopathology Center, Nationwide Children's Hospital, Columbus, OH

11. 11Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, Cornell University, New York, NY

12. 12Infectious Disease Research Institute, Seattle, WA

13. 13Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY

14. 14Lineberger Comprehensive Cancer Center and Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC

15. 15Clinical Research Directorate, Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute, Frederick, MD

16. 16Departments of Pathology and Pediatrics, The Ohio State University, Columbus, OH

17. 17Sage Bionetworks, Seattle, WA

18. 18Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE

19. 19Center for Global Health, National Cancer Institute, National Institutes of Health, Rockville, MD

20. 20Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA

21. 21Foundation for Burkitt Lymphoma Research, Geneva, Switzerland

22. 22Laboratory of Pathology, Clinical Center, National Cancer Institute, National Institutes of Health, Bethesda, MD

23. 23Office of HIV/AIDS Malignancies, National Cancer Institute, National Institutes of Health, Bethesda, MD

24. 24Programa de Oncovirologia, Instituto Nacional de Cancer Jose de Alencar, Rio de Janeiro, Brazil

25. 25University of North Carolina at Chapel Hill, Chapel Hill, NC

26. 26Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD

27. 27Center for Clinical AIDS Research and Education, University of California Los Angeles, Los Angeles, CA

28. 28Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD

29. 29Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN

30. 30Canada's Michael Smith Genome Sciences Centre at BC Cancer, Vancouver, BC, Canada

31. 31Uganda Cancer Institute, Kampala, Uganda

32. 32Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY

33. 33EMBLEM Study, St. Mary's Hospital Lacor, Gulu, Uganda

34. 34Department of Clinical Pathology, Robert-Bosch-Krankenhaus and Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany

35. 35Department of Medicine, Division of Hematology, University of Miami, Sylvester Comprehensive Cancer Center, Miami, FL

36. 36Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD

37. 37Section of Hematology/Oncology, John H. Stroger Jr Hospital of Cook County, Chicago, IL

38. 38Tygerberg Academic Hospital and Stellenbosch University, Cape Town, South Africa

39. 39Division of Hematopathology, University of Pittsburgh School of Medicine, Pittsburgh, PA

40. 40Hospices Civils de Lyon, Université Lyon 1, Service d'Anatomie Pathologique, Hopital Lyon Sud France

41. 41The Cancer Genome Atlas, Center for Cancer Genomics, National Cancer Institute, National Institutes of Health, Bethesda, MD

42. 42Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada

Abstract

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.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

Reference43 articles.

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