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PMID: 10954754 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Ongoing immunoglobulin somatic mutation in germinal center B cell-like but not in activated B cell-like diffuse large cell lymphomas.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 97 ·No. 18 ·2000-08-29 ·Pages 10209-13

Lossos IS, Alizadeh AA, Eisen MB, Chan WC, Brown PO, Botstein D, Staudt LM, Levy R

Abstract

B cell diffuse large cell lymphoma (B-DLCL) is a heterogeneous group of tumors, based on significant variations in morphology, clinical presentation, and response to treatment. Gene expression profiling has revealed two distinct tumor subtypes of B-DLCL: germinal center B cell-like DLCL and activated B cell-like DLCL. In a separate study, we determined that B-DLCL can also be subdivided into two groups based on the presence or absence of ongoing Ig gene hypermutation. Here, we evaluated the correlation between these B-DLCL subtypes established by the two different methods. Fourteen primary B-DLCL cases were studied by gene expression profiling using DNA microarrays and for the presence of ongoing mutations in their Ig heavy chain gene. All seven cases classified as germinal center B cell-like DLCL by gene expression showed the presence of ongoing mutations in the Ig genes. Five of the seven cases classified by gene expression as activated B cell-like DLCL had no ongoing somatic mutations, whereas, in the remaining two cases, a single point mutation was observed in only 2 of 15 and 21 examined molecular clones of variable heavy (V(H)) chain gene, respectively. These two cases were distantly related to the rest of the activated B cell-like DLCL tumors by gene expression. Our findings validate the concept that lymphoid malignancies are derived from cells at discrete stages of normal lymphocyte maturation and that the malignant cells retain the genetic program of those normal cells.

MeSH Terms
Biopsy Genes, Immunoglobulin Humans Immunoglobulin Heavy Chains/genetics Immunoglobulin Variable Region/genetics Lymphoma, B-Cell/classification,genetics,immunology,pathology Lymphoma, Large B-Cell, Diffuse/classification,genetics,immunology,pathology Molecular Sequence Data Mutation Oligonucleotide Array Sequence Analysis
Chemicals
Immunoglobulin Heavy Chains Immunoglobulin Variable Region
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Lossos I S
Departments of Medicine, Biochemistry, and Genetics, Division of Oncology and Howard Hughes Medical Institute, Stanford University Medical Center, Stanford, CA 94305-5306, USA.
Alizadeh A A
Eisen M B
Chan W C
Brown P O
Botstein D
Staudt L M
Levy R
References (32)
32 references, click to expand
  1. Frequent somatic hypermutation of the 5' noncoding region of the BCL6 gene in B-cell lymphoma.
    Proc Natl Acad Sci U S A. 1995 Dec 19;92(26):12520-4 PMID: 8618933
  2. Preferential use of the VH4 Ig gene family by diffuse large-cell lymphoma.
    Blood. 1995 Oct 15;86(8):3072-82 PMID: 7579401
  3. Clonal selection and learning in the antibody system.
    Nature. 1996 Jun 27;381(6585):751-8 PMID: 8657279
  4. Diffuse large cell lymphomas are derived from mature B cells carrying V region genes with a high load of somatic mutation and evidence of selection for antibody expression.
    Eur J Immunol. 1997 Jun;27(6):1398-405 PMID: 9209491
  5. Detection of minimal disease using rearranged immunoglobulin heavy chain genes from intermediate- and high-grade malignant B cell non-Hodgkins lymphoma.
    Leukemia. 1997 Oct;11(10):1742-52 PMID: 9324296
  6. Molecular analysis of the immunoglobulin VH gene rearrangement in a primary cutaneous immunoblastic B-cell lymphoma by micromanipulation and single-cell PCR.
    J Invest Dermatol. 1997 Oct;109(4):541-5 PMID: 9326387
  7. De novo CD5+ diffuse large B-cell lymphomas express VH genes with somatic mutation.
    Blood. 1998 Feb 15;91(4):1145-51 PMID: 9454743
  8. Analysis of VH genes in follicular and diffuse lymphoma shows ongoing somatic mutation and multiple isotype transcripts in early disease with changes during disease progression.
    Blood. 1998 Jun 1;91(11):4292-9 PMID: 9596678
  9. Somatic hypermutation in normal and transformed human B cells.
    Immunol Rev. 1998 Apr;162:261-80 PMID: 9602370
  10. CD10 expression in follicular lymphoma and large cell lymphoma is different from that of reactive lymph node follicles.
    Arch Pathol Lab Med. 1998 Jun;122(6):539-44 PMID: 9625422
  11. Mutation of BCL-6 gene in normal B cells by the process of somatic hypermutation of Ig genes.
    Science. 1998 Jun 12;280(5370):1750-2 PMID: 9624052
  12. Molecular pathological analysis of testicular diffuse large cell lymphomas.
    Hum Pathol. 1998 Nov;29(11):1231-9 PMID: 9824100
  13. Cluster analysis and display of genome-wide expression patterns.
    Proc Natl Acad Sci U S A. 1998 Dec 8;95(25):14863-8 PMID: 9843981
  14. DNA arrays for analysis of gene expression.
    Methods Enzymol. 1999;303:179-205 PMID: 10349646
  15. Primary diffuse large B cell lymphoma of the stomach: analysis of somatic mutations in the rearranged immunoglobulin heavy chain variable genes indicates antigen selection.
    Leukemia. 1999 Jul;13(7):1085-92 PMID: 10400425
  16. Common and HIV-related diffuse large B-cell lymphomas differ in their immunoglobulin gene mutation pattern.
    J Pathol. 1999 Jun;188(2):133-8 PMID: 10398155
  17. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia.
    Blood. 1999 Sep 15;94(6):1840-7 PMID: 10477712
  18. Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia.
    Blood. 1999 Sep 15;94(6):1848-54 PMID: 10477713
  19. V(H) gene sequences from primary central nervous system lymphomas indicate derivation from highly mutated germinal center B cells with ongoing mutational activity.
    Blood. 1999 Sep 1;94(5):1738-46 PMID: 10477699
  20. Molecular and immunological dissection of diffuse large B cell lymphoma: CD5+, and CD5- with CD10+ groups may constitute clinically relevant subtypes.
    Leukemia. 1999 Sep;13(9):1441-7 PMID: 10482997
  21. Mutation analysis of the 5' noncoding regulatory region of the BCL-6 gene in non-Hodgkin lymphoma: evidence for recurrent mutations and intraclonal heterogeneity.
    Blood. 2000 Feb 15;95(4):1400-5 PMID: 10666217
  22. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling.
    Nature. 2000 Feb 3;403(6769):503-11 PMID: 10676951
  23. Molecular analysis of immunoglobulin genes in diffuse large B-cell lymphomas.
    Blood. 2000 Mar 1;95(5):1797-803 PMID: 10688840
  24. Germinal centers develop oligoclonally.
    Eur J Immunol. 1987 Jul;17(7):1069-72 PMID: 3301368
  25. Ig VH gene expression among human follicular lymphomas.
    Blood. 1991 Sep 15;78(6):1561-8 PMID: 1909196
  26. Sites of specific B cell activation in primary and secondary responses to T cell-dependent and T cell-independent antigens.
    Eur J Immunol. 1991 Dec;21(12):2951-62 PMID: 1748148
  27. Absence of immunoglobulin variable region hypermutation in a large cell lymphoma after in vivo and in vitro propagation.
    Blood. 1992 Aug 1;80(3):738-43 PMID: 1638025
  28. Clonal evolution of a follicular lymphoma: evidence for antigen selection.
    Proc Natl Acad Sci U S A. 1992 Aug 1;89(15):6770-4 PMID: 1495966
  29. Germinal centers.
    Annu Rev Immunol. 1994;12:117-39 PMID: 8011279
  30. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group.
    Blood. 1994 Sep 1;84(5):1361-92 PMID: 8068936
  31. Immunoglobulin heavy chain variable gene utilization in human large cell and Burkitt's lymphoma cell lines.
    Clin Invest Med. 1994 Dec;17(6):522-30 PMID: 7895416
  32. BCL-6 expression during B-cell activation.
    Blood. 1996 Jun 15;87(12):5257-68 PMID: 8652841
Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.180316097
Published
2000-08-29
Pages
10209-13
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC27813
Subset
IM
Grants
NCI NIH HHS · U01 CA084967 · United States
NCI NIH HHS · UO1 CA84967 · United States
NCI NIH HHS · P01 CA034233 · United States
NCI NIH HHS · CA34233 · United States
NCI NIH HHS · CA33399 · United States
NCI NIH HHS · R37 CA033399 · United States
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GENBANK
AF283779, AF283780, AF283781, AF283782, AF283783, AF283784, AF283785, AF283786, AF283787, AF283788, AF283789, AF283790, AF283791, AF283792, AF283793, AF283794, AF283795, AF283796, AF283797, AF283798, AF283799, AF283800, AF283801, AF283802, AF283803, AF283804, AF283805, AF283806, AF283807
External Links
PubMed source DOI: 10.1073/pnas.180316097 PMC Full Text View journal details
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