RESUMO
In myeloma, the prognostic impact of different strategies used to detect chromosome 13 deletion (Delta13) remains controversial. To address this, we compared conventional cytogenetics and interphase fluorescence in situ hybridization (iFISH) in a large multicenter study (n=794). The ability to obtain abnormal metaphases was associated with a poor prognosis, which was worse if Delta13, p53 deletion or t(4;14) was present, but only Delta13 remained significant on multivariate analysis. Patients with Delta13, by either cytogenetics or iFISH, had a poor prognosis. However, when cases with Delta13 detectable by both cytogenetics and iFISH were separated from those detected by iFISH only, the poor prognosis of iFISH-detectable Delta13 disappeared; their outcome matched that of patients with no detectable Delta13 (P=0.115). Addition of ploidy status to iFISH-Delta13 did not affect the prognostic value of the test. Indeed both cytogenetics and iFISH Delta13 divided both hyperdiploidy and nonhyperdiploidy into two groups with similar prognoses, indicating that the poor prognosis of ploidy is entirely due to its association with Delta13. We conclude that Delta13 detected by metaphase analysis is a critical prognostic factor in myeloma. Absence of Delta13, even in those patients yielding only normal or no metaphases, is associated with a relatively good prognosis.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 13 , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Genes de Cadeia Pesada de Imunoglobulina , Genes p53 , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Ploidias , Prognóstico , Análise de Sobrevida , Translocação GenéticaRESUMO
A simple high throughput micro-fluorescence in situ hybridisation technique (FISH) was used to detect chromosome 13 deletions (delta13), immunoglobulin heavy chain (IgH) rearrangements, t(11;14)(q13;q32), t(4;14)(p16;q32), t(14;16)(q23;q32), p53 loss, and numerical changes of chromosomes 3, 6, 7, 9, 10, 11 and 17 in 228 cases of multiple myeloma (MM), including 33 asymptomatic/smouldering MM (SMM). The patients were not part of a clinical trial and were from 30 different hospitals. In all, 98.4% of cases were abnormal, with 43% having IgH rearrangements and 42% Delta13. The low incidence of IgH rearrangements was due to a decrease in this finding with age (P = 0.001) and the relatively high proportion of elderly patients in our study population (41% >70 years old). The incidence of specific IgH translocations was t(4;14) 11%, t(11;14) 16% and t(14;16) 3%. Univariate statistical testing showed delta13 (P = 0.002), and t(14;16) (P = 0.005) to be associated with shorter survival. This effect was exaggerated for patient's aged 70 years or under but no effect on survival was seen for those over 70 years. In younger patients t(4;14) (P = 0.044) and p53 deletion (P < 0.001) were also significant poor prognostic indicators. Multivariate analysis showed delta13 and t(14;16) to be independent prognostic variables when considered with age and clinical parameters.
Assuntos
Aberrações Cromossômicas , Mieloma Múltiplo/genética , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Seguimentos , Humanos , Hibridização in Situ Fluorescente/métodos , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/patologia , Estudos Retrospectivos , Análise de SobrevidaRESUMO
Acquired uniparental disomy (aUPD) is a common finding in myeloid malignancies and typically acts to convert a somatically acquired heterozygous mutation to homozygosity. We sought to identify the target of chromosome 14 aUPD (aUPD14), a recurrent abnormality in myeloid neoplasms and population cohorts of elderly individuals. We identified 29 cases with aUPD14q that defined a minimal affected region (MAR) of 11.2 Mb running from 14q32.12 to the telomere. Exome sequencing (n=7) did not identify recurrently mutated genes, but methylation-specific PCR at the imprinted MEG3-DLK1 locus located within the MAR demonstrated loss of maternal chromosome 14 and gain of paternal chromosome 14 (P<0.0001), with the degree of methylation imbalance correlating with the level of aUPD (r=0.76; P=0.0001). The absence of driver gene mutations in the exomes of three individuals with aUPD14q but no known haematological disorder suggests that aUPD14q may be sufficient to drive clonal haemopoiesis. Analysis of cases with both aUPD14q and JAK2 V617F (n=11) indicated that aUPD14q may be an early event in some cases but a late event in others. We conclude that aUPD14q is a recurrent abnormality that targets an imprinted locus and may promote clonal haemopoiesis either as an initiating event or as a secondary change.
Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 14/genética , Impressão Genômica , Síndromes Mielodisplásicas/genética , Transtornos Mieloproliferativos/genética , Pais , Dissomia Uniparental/genética , Metilação de DNA , Exoma/genética , Heterozigoto , Homozigoto , Humanos , Mutação/genética , Polimorfismo de Nucleotídeo Único/genética , PrognósticoRESUMO
The association of genetic lesions detected by fluorescence in situ hybridization (FISH) with survival was analyzed in 1069 patients with newly presenting myeloma treated in the Medical Research Council Myeloma IX trial, with the aim of identifying patients associated with the worst prognosis. A comprehensive FISH panel was performed, and the lesions associated with short progression-free survival and overall survival (OS) in multivariate analysis were +1q21, del(17p13) and an adverse immunoglobulin heavy chain gene (IGH) translocation group incorporating t(4;14), t(14;16) and t(14;20). These lesions frequently co-segregated, and there was an association between the accumulation of these adverse FISH lesions and a progressive impairment of survival. This observation was used to define a series of risk groups based on number of adverse lesions. Taking this approach, we defined a favorable risk group by the absence of adverse genetic lesions, an intermediate group with one adverse lesion and a high-risk group defined by the co-segregation of >1 adverse lesion. This genetic grouping was independent of the International Staging System (ISS) and so was integrated with the ISS to identify an ultra-high-risk group defined by ISS II or III and >1 adverse lesion. This group constituted 13.8% of patients and was associated with a median OS of 19.4 months.