title: Aberrant somatic hypermutation in tumor cells of nodular-lymphocyte-predominant and classic Hodgkin lymphoma.
abstract: 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, 1.04/1,000 bp) and 35 were detected in patients with cHL (frequency, 1.92/1,000 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.
authors.affiliation: Institute of Hematology, University of Perugia, Policlinico, Monteluce, 06122 Perugia, Italy.
authors.forename: Arcangelo
authors.initials: A
authors.lastname: Liso
authors.forename: Daniela
authors.initials: D
authors.lastname: Capello
authors.forename: Teresa
authors.initials: T
authors.lastname: Marafioti
authors.forename: Enrico
authors.initials: E
authors.lastname: Tiacci
authors.forename: Michaela
authors.initials: M
authors.lastname: Cerri
authors.forename: Verena
authors.initials: V
authors.lastname: Distler
authors.forename: Marco
authors.initials: M
authors.lastname: Paulli
authors.forename: Antonino
authors.initials: A
authors.lastname: Carbone
authors.forename: Georges
authors.initials: G
authors.lastname: Delsol
authors.forename: Elias
authors.initials: E
authors.lastname: Campo
authors.forename: Stefano
authors.initials: S
authors.lastname: Pileri
authors.forename: Laura
authors.initials: L
authors.lastname: Pasqualucci
authors.forename: Gianluca
authors.initials: G
authors.lastname: Gaidano
authors.forename: Brunangelo
authors.initials: B
authors.lastname: Falini
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D006689:Hodgkin Disease / Q000209:etiology* / Q000235:genetics / Q000473:pathology*; D006801:Humans; D008198:Lymph Nodes / Q000473:pathology*; D008214:Lymphocytes / Q000473:pathology*; D016393:Lymphoma, B-Cell / Q000209:etiology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000209:etiology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D051757:PAX5 Transcription Factor / Q000235:genetics; D027041:Somatic Hypermutation, Immunoglobulin
chemical_list: D051757:PAX5 Transcription Factor; C497281:PAX5 protein, human