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Prepublished online as a Blood First Edition Paper on April 24, 2003; DOI 10.1182/blood-2002-11-3606.
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Blood, 1 September 2003, Vol. 102, No. 5, pp. 1833-1841
NEOPLASIA
Aberrant somatic hypermutation in multiple subtypes of AIDS-associated non-Hodgkin lymphoma
Gianluca Gaidano,
Laura Pasqualucci,
Daniela Capello,
Eva Berra,
Clara Deambrogi,
Davide Rossi,
Luigi Maria Larocca,
Annunziata Gloghini,
Antonino Carbone, and
Riccardo Dalla-Favera
From the Hematology Unit, Division of Internal Medicine, Department of
Medical Sciences and Interdisciplinary Research Center on Autoimmune Diseases
(IRCAD), Amedeo Avogadro University of Eastern Piedmont, Novara, Italy;
Institute for Cancer Genetics, Columbia University, New York, NY; Institute of
Pathology, Catholic University of the Sacred Heart, Rome, Italy; and Division
of Pathology, Centro di Riferimento Oncologico, Istituto Nazionale Tumori,
Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Aviano,
Italy.
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.
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