RESUMO
The acquisition of the cytogenetic abnormalities hyperdiploidy or translocations into the immunoglobulin gene loci are considered as initiating events in the pathogenesis of myeloma and were often assumed to be mutually exclusive. These lesions have clinical significance; hyperdiploidy or the presence of the t(11;14) translocation is associated with a favorable outcome, whereas t(4;14), t(14;16), and t(14;20) are unfavorable. Poor outcomes are magnified when lesions occur in association with other high-risk features, del17p and +1q. Some patients have coexistence of both good and poor prognostic lesions, and there has been no consensus on their risk status. To address this, we have investigated their clinical impact using cases in the Myeloma IX study (ISRCTN68454111) and shown that the coexistence of hyperdiploidy or t(11;14) does not abrogate the poor prognosis associated with adverse molecular lesions, including translocations. We have also used single-cell analysis to study cases with coexistent translocations and hyperdiploidy to determine how these lesions cosegregate within the clonal substructure, and we have demonstrated that hyperdiploidy may precede IGH translocation in a proportion of patients. These findings have important clinical and biological implications, as we conclude patients with coexistence of adverse lesions and hyperdiploidy should be considered high risk and treated accordingly.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Diploide , Regulação Neoplásica da Expressão Gênica , Cadeias Pesadas de Imunoglobulinas/genética , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Translocação Genética , Idoso , Cromossomos Humanos Par 11 , Cromossomos Humanos Par 14 , Cromossomos Humanos Par 16 , Cromossomos Humanos Par 20 , Cromossomos Humanos Par 4 , Análise Citogenética , Feminino , Humanos , Cadeias Pesadas de Imunoglobulinas/imunologia , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/mortalidade , Prognóstico , Transdução de Sinais , Análise de Célula Única , Análise de SobrevidaAssuntos
Cromossomos Humanos Par 7 , Regulação Neoplásica da Expressão Gênica , Fatores Reguladores de Interferon/genética , Mieloma Múltiplo/genética , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Repressoras/genética , Idoso , Alelos , Sítios de Ligação , Mapeamento Cromossômico , Feminino , Humanos , Fatores Reguladores de Interferon/metabolismo , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Plasmócitos/metabolismo , Plasmócitos/patologia , Polimorfismo de Nucleotídeo Único , Ligação Proteica , Proteínas Proto-Oncogênicas c-myc/metabolismo , Locos de Características Quantitativas , Proteínas Repressoras/metabolismo , Transdução de SinaisRESUMO
Monoclonal gammopathy of undetermined significance (MGUS) is present in â¼2% of individuals age >50 years. The increased risk of multiple myeloma (MM) in relatives of individuals with MGUS is consistent with MGUS being a marker of inherited genetic susceptibility to MM. Common single-nucleotide polymorphisms (SNPs) at 2p23.3 (rs6746082), 3p22.1 (rs1052501), 3q26.2 (rs10936599), 6p21.33 (rs2285803), 7p15.3 (rs4487645), 17p11.2 (rs4273077), and 22q13.1 (rs877529) have recently been shown to influence MM risk. To examine the impact of these 7 SNPs on MGUS, we analyzed two case-control series totaling 492 cases and 7306 controls. Each SNP independently influenced MGUS risk with statistically significant associations (P < .02) for rs1052501, rs2285803, rs4487645, and rs4273077. SNP associations were independent, with risk increasing with a larger number of risk alleles carried (per allele odds ratio, 1.18; P < 10(-7)). Collectively these data are consistent with a polygenic model of disease susceptibility to MGUS.
Assuntos
Gamopatia Monoclonal de Significância Indeterminada/genética , Mieloma Múltiplo/genética , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Alemanha/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Gamopatia Monoclonal de Significância Indeterminada/epidemiologia , Gamopatia Monoclonal de Significância Indeterminada/patologia , Mieloma Múltiplo/epidemiologia , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Translocations in myeloma are thought to occur solely in mature B cells in the germinal center through class switch recombination (CSR). We used a targeted captured technique followed by massively parallel sequencing to determine the exact breakpoints in both the immunoglobulin heavy chain (IGH) locus and the partner chromosome in 61 presentation multiple myeloma samples. The majority of samples (62%) have a breakpoint within the switch regions upstream of the IGH constant genes and are generated through CSR in a mature B cell. However, the proportion of CSR translocations is not consistent between cytogenetic subgroups. We find that 100% of t(4;14) are CSR-mediated; however, 21% of t(11;14) and 25% of t(14;20) are generated through DH-JH recombination activation gene-mediated mechanisms, indicating they occur earlier in B-cell development at the pro-B-cell stage in the bone marrow. These 2 groups also generate translocations through receptor revision, as determined by the breakpoints and mutation status of the segments used in 10% and 50% of t(11;14) and t(14;20) samples, respectively. The study indicates that in a significant number of cases the translocation-based etiological events underlying myeloma may arise at the pro-B-cell hematological progenitor cell level, much earlier in B-cell development than was previously thought.
