RESUMO
We performed an immunogenetic analysis of 345 IGHV-IGHD-IGHJ rearrangements from 337 cases with primary splenic small B-cell lymphomas of marginal-zone origin. Three immunoglobulin (IG) heavy variable (IGHV) genes accounted for 45.8% of the cases (IGHV1-2, 24.9%; IGHV4-34, 12.8%; IGHV3-23, 8.1%). Particularly for the IGHV1-2 gene, strong biases were evident regarding utilization of different alleles, with 79/86 rearrangements (92%) using allele (*)04. Among cases more stringently classified as splenic marginal-zone lymphoma (SMZL) thanks to the availability of splenic histopathological specimens, the frequency of IGHV1-2(*)04 peaked at 31%. The IGHV1-2(*)04 rearrangements carried significantly longer complementarity-determining region-3 (CDR3) than all other cases and showed biased IGHD gene usage, leading to CDR3s with common motifs. The great majority of analyzed rearrangements (299/345, 86.7%) carried IGHV genes with some impact of somatic hypermutation, from minimal to pronounced. Noticeably, 75/79 (95%) IGHV1-2(*)04 rearrangements were mutated; however, they mostly (56/75 cases; 74.6%) carried few mutations (97-99.9% germline identity) of conservative nature and restricted distribution. These distinctive features of the IG receptors indicate selection by (super)antigenic element(s) in the pathogenesis of SMZL. Furthermore, they raise the possibility that certain SMZL subtypes could derive from progenitor populations adapted to particular antigenic challenges through selection of VH domain specificities, in particular the IGHV1-2(*)04 allele.
Assuntos
Regiões Determinantes de Complementaridade/genética , Rearranjo Gênico de Cadeia Pesada de Linfócito B , Genes de Cadeia Pesada de Imunoglobulina/genética , Região Variável de Imunoglobulina/genética , Linfoma de Zona Marginal Tipo Células B/genética , Neoplasias Esplênicas/genética , Estudos de Coortes , Humanos , Modelos Moleculares , Mutação/genética , PrognósticoAssuntos
Perfilação da Expressão Gênica , Leucemia de Células Pilosas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Aberrações Cromossômicas , Terapia Combinada , DNA de Neoplasias/genética , Feminino , Dosagem de Genes , Genes Neoplásicos , Genes Supressores de Tumor , Humanos , Leucemia de Células Pilosas/classificação , Leucemia de Células Pilosas/tratamento farmacológico , Leucemia de Células Pilosas/cirurgia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , EsplenectomiaAssuntos
Apoptose/efeitos dos fármacos , Proteínas de Choque Térmico HSP72/antagonistas & inibidores , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/patologia , Protocolos de Quimioterapia Combinada Antineoplásica , Compostos Benzidrílicos/farmacologia , Benzoquinonas/farmacologia , Western Blotting , Ciclo Celular , Proliferação de Células , Sinergismo Farmacológico , Proteínas de Choque Térmico HSP72/genética , Proteínas de Choque Térmico HSP72/metabolismo , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Lactamas Macrocíclicas/farmacologia , Mieloma Múltiplo/metabolismo , Pirrolidinonas/farmacologia , RNA Mensageiro/genética , RNA Interferente Pequeno/farmacologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Transcrição CHOP/genética , Fator de Transcrição CHOP/metabolismo , Células Tumorais CultivadasAssuntos
Citidina Desaminase/genética , Variação Genética , Leucemia de Células Pilosas/genética , Linfoma de Zona Marginal Tipo Células B/genética , Neoplasias Esplênicas/genética , Western Blotting , Diferenciação Celular , Citidina Desaminase/metabolismo , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Região Variável de Imunoglobulina/genética , Imunofenotipagem , Leucemia de Células Pilosas/metabolismo , Leucemia de Células Pilosas/patologia , Linfoma de Zona Marginal Tipo Células B/metabolismo , Linfoma de Zona Marginal Tipo Células B/patologia , Mutação/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Neoplasias Esplênicas/metabolismo , Neoplasias Esplênicas/patologiaRESUMO
Somatic mutations of the KIT gene have been reported in mast cell diseases and gastrointestinal stromal tumours. Recently, they have also been found in mediastinal and testicular germ cell tumours (TGCTs), particularly in cases with bilateral disease. We screened the KIT coding sequence (except exon 1) for germline mutations in 240 pedigrees with two or more cases of TGCT. No germline mutations were found. Exons 10, 11 and 17 of KIT were examined for somatic mutations in 123 TGCT from 93 multiple-case testicular cancer families. Five somatic mutations were identified; four were missense amino-acid substitutions in exon 17 and one was a 12 bp in-frame deletion in exon 11. Two of seven TGCT from cases with bilateral disease carried KIT mutations compared with three out of 116 unilateral cases (P=0.026). The results indicate that somatic KIT mutations are implicated in the development of a minority of familial as well as sporadic TGCT. They also lend support to the hypothesis that KIT mutations primarily take place during embryogenesis such that primordial germ cells with KIT mutations are distributed to both testes.