Aberrant somatic hypermutation in multiple subtypes of AIDS-associated non-Hodgkin lymphoma.
The pathogenesis of AIDS-related non-Hodgkin lymphomas (AIDS-NHLs) is associated with chromosomal translocations that deregulate the expression of various oncogenes. Recently, a novel mechanism of genetic lesion, termed aberrant hypermutation, has been identified in diffuse large B-cell lymphoma (DLBCL) of immunocompetent hosts. In these tumors, the somatic hypermutation (SHM) process that normally targets immunoglobulin V (IgV) genes in B cells appears to misfire and causes mutations in the 5' sequences of multiple proto-oncogenes, including PIM-1, PAX-5, RhoH/TTF, and c-MYC. To investigate whether aberrant hypermutation occurs also in AIDS-NHL, we studied the mutation profile of these 4 genes in various histologic subtypes. Mutations in 1 gene or more were detected in 19 of 39 (48.7%) AIDS-NHL cases (10 of 18 AIDS-diffuse large B-cell lymphoma; 4 of 11 AIDS-Burkitt lymphoma; 4 of 6 AIDS-primary effusion lymphoma; 1 of 4 AIDS-primary central nervous system lymphoma), with 9 of 39 (23.1%) cases carrying mutations in 2 or more genes. Overall, PIM-1 was mutated in 5 of 39 (12.8%), PAX-5 in 8 of 39 (20.5%), RhoH/TTF in 9 of 39 (23.1%), and c-MYC in 7 of 27 (25.9%) AIDS-NHL cases. Mutations were represented mainly by single base pair substitutions (n = 63) with rare deletions/insertions (n = 5) and displayed features typical of the IgV-associated SHM process. In addition, a number of mutations in PIM-1 and c-MYC were found to affect coding exons, leading to amino acid substitutions with likely functional consequences. Analysis of intraclonal heterogeneity documented that the aberrant hypermutation activity may be ongoing in at least some cases. These data indicate that aberrant hypermutation is associated with various subtypes of AIDS-NHL and may represent a major contributor to their pathogenesis.
Gaidano
Gianluca
G
Institute for Cancer Genetics, Columbia University, Russ Berrie Science Pavilion, 1150 St Nicholas Ave, Rm 303B, New York, NY 10032, USA.
Pasqualucci
Laura
L
Capello
Daniela
D
Berra
Eva
E
Deambrogi
Clara
C
Rossi
Davide
D
Maria Larocca
Luigi
L
Gloghini
Annunziata
A
Carbone
Antonino
A
Dalla-Favera
Riccardo
R
D000595:Amino Acid Sequence; D001402:B-Lymphocytes / Q000502:physiology; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000235:genetics; D016483:Lymphoma, AIDS-Related / Q000235:genetics* / Q000276:immunology*; D008228:Lymphoma, Non-Hodgkin / Q000235:genetics* / Q000276:immunology*; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D051757:PAX5 Transcription Factor; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051560:Proto-Oncogene Proteins c-bcl-6; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D051573:Proto-Oncogene Proteins c-pim-1; D027041:Somatic Hypermutation, Immunoglobulin; D014157:Transcription Factors / Q000235:genetics; D020741:rho GTP-Binding Proteins / Q000235:genetics
D004268:DNA-Binding Proteins; D007135:Immunoglobulin Variable Region; D051757:PAX5 Transcription Factor; C497281:PAX5 protein, human; D011518:Proto-Oncogene Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D016271:Proto-Oncogene Proteins c-myc; C447841:RhoH protein, human; D014157:Transcription Factors; C496634:PIM1 protein, human; D017346:Protein Serine-Threonine Kinases; D051573:Proto-Oncogene Proteins c-pim-1; D020741:rho GTP-Binding Proteins