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Blood, 1 August 2006, Vol. 108, No. 3, pp. 1013-1020.
Prepublished online as a Blood First Edition Paper on April 13, 2006; DOI 10.1182/blood-2005-10-3949.
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NEOPLASIA
Aberrant somatic hypermutation in tumor cells of nodular-lymphocyte–predominant and classic Hodgkin lymphoma
Arcangelo Liso,
Daniela Capello,
Teresa Marafioti,
Enrico Tiacci,
Michaela Cerri,
Verena Distler,
Marco Paulli,
Antonino Carbone,
Georges Delsol,
Elias Campo,
Stefano Pileri,
Laura Pasqualucci,
Gianluca Gaidano, and
Brunangelo Falini
From the Institute of Hematology, University of Perugia, Italy; Institute of Hematology, University of Foggia, Italy; Division of Hematology, Department of Clinical and Experimental Medicine, University of Eastern Piedmont, Novara, Italy; Nuffield Department of Clinical Laboratory Sciences, University of Oxford, United Kingdom; Institute for Pathology, University of Frankfurt, Germany; Section of Molecular Genetics, Institute for Cell Biology–Tumor Research, University of Duisburg-Essen Medical School, Essen, Germany; Anatomic Pathology Department, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico S. Matteo, Pavia, Italy; Dipartimento di Anatomia Patologica, Istituto Nazionale Tumori, Milano, Italy; Centre de Physiopathologie de Toulouse Purpan, (CPTP), Institut National de la Santé et de la Recherche Médicale (INSERM) U563, Centre Hospitalier Universitaire (CHU) Purpan, Toulouse, France; Hematopathology Section, University of Barcelona, Spain; Hematopathology Section, Policlinico S. Orsola, Bologna, Italy; and Institute for Cancer Genetics, Columbia University, New York, NY.
Aberrant somatic hypermutation (SHM) has been identified as a mechanism for genomewide instability in diffuse large B-cell lymphoma (DLBCL). To assess whether aberrant SHM plays a role in the molecular pathogenesis of Hodgkin lymphoma (HL), we investigated microdissected neoplastic cells of nodular lymphocyte-predominant HL (NLPHL; n = 10) and classic HL (cHL; n = 9) for the presence of mutations in the 5' sequences of 4 previously identified aberrant SHM targets (PIM1, PAX5, RhoH/TTF, c-MYC). Mutations in one or more genes were detected in 80% of NLPHLs and 55% of cHLs, with 50% and 30% of patients carrying mutations in 2 or more genes, respectively. The most frequently involved protooncogene was PAX5, mutated in 7 of 9 patients with NLPHL and 2 of 9 patients with cHL. In total, 34 mutations were detected in NLPHL (frequency, 1.04/1000 bp) and 35 were detected in patients with cHL (frequency, 1.92/1000 bp). Mutations were of somatic origin because they were absent in control T cells and shared most of the features of the immunoglobulin variable (IGV) gene–associated SHM mechanism—ie, single nucleotide substitutions (n = 63) with rare deletions/insertions (n = 6) and a predominance of transitions over transversions with preferential targeting motifs. Our finding that NLPHL and cHL are targeted by aberrant SHM, as is DLBCL, suggests that these lymphomas may share common molecular pathogenetic events.
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