RESUMO
The mutational status of the variable region of the immunoglobulin heavy chain (IGHV) genes remains the most significant prognostic factor in chronic lymphocytic leukemia (CLL) patients. However, the groups of mutated (M) and unmutated (UM) patients are also heterogeneous, and additional markers are used for a more accurate prognosis. The aim of our work was to determine the prognostic value of the signs of antigen selection determined by BASELINe statistics in M IGHV sequences of CLL patients. Clinical data, IGHV gene configuration, TP53, NOTCH1, SF3B1 mutations were analyzed in 127 CLL patients with M IGHV sequences. The median OS of patients with negative selection in the framework regions (FWRs) of IGHV genes was 120 months compared to 202 month in other CLL patients (P = 0.016). In multivariate Cox regression analysis Binet stage C vs A + B (P < 0.0001), SF3B1 mutations (P < 0.0001), negative selection in the FWRs (HR P = 0.007), and age ≥65 years (P = 0.034) were powerful adverse prognostic factors for OS in CLL patients with M IGHV genes. These preliminary data suggest that the signs of antigen-driven selection may be used as a prognostic factor in CLL patients with M IGHV genes in combination with other markers.
Assuntos
Biomarcadores Tumorais/genética , Cadeias Pesadas de Imunoglobulinas/genética , Região Variável de Imunoglobulina/genética , Leucemia Linfocítica Crônica de Células B/mortalidade , Mutação , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de SobrevidaRESUMO
OBJECTIVES: To analyze the distribution of single nucleotide polymorphisms (SNPs) in the TP53 gene in chronic lymphocytic leukemia (CLL) patients and to evaluate their associations with clinical behavior of the disease. METHODS: SNPs in exons and parts of adjacent introns of the TP53 gene were analyzed in 235 CLL patients observed during 2005-2012 years. Data on individuals of European descent from the 1000 Genomes Project data set were used as a reference. RESULTS: In the recessive model of inheritance, we found borderline associations between CLL risk and C/C genotype of rs1642785 (p=0.048); G/G genotype of rs2909430 (in men only; p=0.036) and Pro72Pro genotype of rs1042522 (in men only; p=0.045). Risk of CLL was increased also in carriers of rare haplotypes (p=0.0049). Besides, genotypes Pro72Pro of rs1042522, C/C of rs1642785, and G/G of rs2909430 were associated with an increased incidence of TP53 mutations. Median of overall survival in rs1800372 carriers was comparable to that of patients with TP53 mutations. Other evaluated SNPs were not associated with survival. CONCLUSION: Our data suggest that some TP53 variants may affect the risk of CLL. rs1800372 polymorphism might be the marker of unfavorable prognosis of the disease.
Assuntos
Leucemia Linfocítica Crônica de Células B/genética , Proteína Supressora de Tumor p53/genética , Adulto , Idoso , Biomarcadores Tumorais/genética , Feminino , Genótipo , Heterozigoto , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mutação , Polimorfismo de Nucleotídeo Único , Prognóstico , Modelos de Riscos ProporcionaisRESUMO
rs6449182 CD38 gene polymorphism was determined by polymerase chain reaction with restriction of products in 328 chronic lymphocytic leukemia (CLL) patients and 271 age- and sex-matched controls. An association between GG genotype and CLL risk was found in the whole group of patients (OR=2.12; p=0.009) and in patients with unmutated immunoglobulin heavy chain variable genes (OR=2.17; p=0.011) comparing to the controls. In the subgroup of 174 controls with evaluated lipids the genotype distributions in CLL patients and dyslipidemic controls were similar. An association between GG genotype and CLL risk was significant compared to controls without lipids' abnormalities (OR=3.92; p=0.006).
Assuntos
ADP-Ribosil Ciclase 1/genética , Leucemia Linfocítica Crônica de Células B/genética , Polimorfismo Genético/genética , Estudos de Casos e Controles , DNA/genética , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Fatores de RiscoRESUMO
An association between DNA repair gene polymorphisms, environmental factors, and development of some types of cancer has been suggested by several studies. Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in the clean-up workers of the Chernobyl Nuclear Power Plant (NPP) accident and it has some specific features. Therefore, we have studied the possible differences in DNA repair gene polymorphisms in CLL patients depending on ionizing radiation (IR) exposure history and their clinical characterictics. Arg399Gln XRCC1, Thr241Met XRCC3, and Lys751Gln XPD polymorphisms were studied in 64 CLL patients, exposed to IR due to the Chernobyl NPP accident, 114 IR-non-exposed CLL patients, and 103 sex- and age-matched IR-exposed controls using polymerase chain reaction-restriction fragment-length polymorphism analysis. All investigated polymorphisms were equally distributed between two groups of CLL patients and IR-exposed controls, except that that there was a significant reduction of the common homozygous Lys/Lys XPD genotype among IR-exposed CLL patients (23.7%) compared with IR-exposed controls (45.6%), OR = 0.37; 95% CI = 0.18-0.75; (P = 0.005). The number of IR-non-exposed CLL patients (37.4%) with the Lys/Lys XPD genotype was also decreased compared to IR-exposed controls, although this difference was not significant (P = 0.223). These preliminary data suggest a possible modifying role of Lys751Gln XPD polymorphism for the development of CLL, expecially in radiation-exposed persons.
Assuntos
Acidente Nuclear de Chernobyl , Reparo do DNA/genética , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Induzida por Radiação/genética , Estudos de Casos e Controles , Feminino , História do Século XX , História do Século XXI , Humanos , Leucemia Linfocítica Crônica de Células B/etiologia , Leucemia Linfocítica Crônica de Células B/história , Leucemia Induzida por Radiação/etiologia , Leucemia Induzida por Radiação/história , Masculino , Pessoa de Meia-Idade , Centrais Nucleares/história , Polimorfismo Genético , Ucrânia , Proteína Grupo D do Xeroderma Pigmentoso/genéticaRESUMO
A fraction of chronic lymphocytic leukemia (CLL) carries highly homologous B-cell receptors, characterized by non-random combinations of immunoglobulin heavy-chain variable (IGHV) genes and heavy-chain complementarity-determining region-3 (HCDR3), often associated with a restricted selection of IG(K/L)V light chains. We analyzed the features of CLL expressing homologous HCDR3 in a cohort of 264 Ukrainian patients by merging them with a recently published reference series of 1426 cases. This approach allowed us to identify 96/264 (36%) cases as expressing homologous HCDR3, subdivided into 47 subsets. Among these, 27 apparently novel subsets were identified, although most of them were composed of two sequences per subset ('potential subsets'). CLL cases belonging to several stereotyped subsets showed HCDR3 homologies with various autoreactive clones. Our analysis identified molecular and clinical features of a Ukrainian cohort of patients with CLL.
Assuntos
Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologia , Receptores de Antígenos de Linfócitos B/genética , Estudos de Coortes , Regiões Determinantes de Complementaridade/genética , Rearranjo Gênico do Linfócito B/genética , Genes de Cadeia Pesada de Imunoglobulina/genética , Humanos , Região Variável de Imunoglobulina/genética , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Hipermutação Somática de Imunoglobulina/genética , Taxa de Sobrevida , Resultado do TratamentoRESUMO
Clinical data and immunoglobulin variable heavy chain (IgVH) gene configuration were analyzed in 47 CLL patients, exposed to ionizing radiation (IR) due to Chernobyl NPP accident, and 141 non-exposed patients. Clean-up workers of the second quarter of 1986 (n=19) were picked out as separate group with the highest number of unmutated cases (94.4%), increased usage of IgVH1-69 (33.3%) and IgVH3-21 (16.7%) genes, high frequency of secondary solid tumors (6 cases) and Richter transformation (4 cases). These preliminary data suggest that CLL in the most suffered contingent due to Chernobyl NPP accident might have some specific features.
Assuntos
Acidente Nuclear de Chernobyl , Expressão Gênica , Cadeias Pesadas de Imunoglobulinas/genética , Região Variável de Imunoglobulina/genética , Leucemia Linfocítica Crônica de Células B/genética , Segunda Neoplasia Primária/genética , Radiação Ionizante , Adulto , Idoso , Estudos de Coortes , Feminino , Rearranjo Gênico , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Taxa de SobrevidaRESUMO
Several studies suggested a causal link between AML1 gene rearrangements and both radiation-induced acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS). Fifty-three AML samples were analyzed for the presence of AML1 abnormalities using fluorescent in-situ hybridization (FISH) and reverse transcription polymerase chain reaction (RT-PCR). Of these patients, 24 had experienced radiation exposure due to the Chernobyl accident, and 29 were non-irradiated spontaneous AML cases and served as controls. AML1/ETO translocations were found in 9 of 29 spontaneous AML but only in 1 of 24 radiation-associated AML cases. This difference between translocation frequencies is statistically significant in the age-unstratified cohorts (p=0.015). Following age stratification, the difference becomes less pronounced but remains on borderline significance (p=0.053). AML1 mutation status was assessed in 5 clean-up workers at Chernobyl NPP with MDS, or AML following MDS, by direct sequencing of genomic DNA from the coding region (exon 3 through 8). In one patient who developed MDS following an acute radiation syndrome, a hexanucleotide duplication of CGGCAT in exon 8 was found, inserted after base position 1502. Our results suggest that AML1 gene translocations are infrequent in radiation-induced leukemogenesis but are consistent with the idea that radiation may contribute to the development of MDS through AML1 gene mutation.
Assuntos
Acidente Nuclear de Chernobyl , Proteínas de Ligação a DNA/genética , Leucemia Mieloide Aguda/epidemiologia , Leucemia Mieloide Aguda/metabolismo , Síndromes Mielodisplásicas/epidemiologia , Síndromes Mielodisplásicas/metabolismo , Neoplasias Induzidas por Radiação/epidemiologia , Neoplasias Induzidas por Radiação/metabolismo , Proteínas Proto-Oncogênicas/genética , Fatores de Transcrição/genética , Adulto , Idoso , Causalidade , Subunidade alfa 2 de Fator de Ligação ao Core , Análise Mutacional de DNA , Feminino , Frequência do Gene , Humanos , Incidência , Leucemia Mieloide Aguda/genética , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/genética , Neoplasias Induzidas por Radiação/genética , Centrais Elétricas , Liberação Nociva de Radioativos , Medição de Risco/métodos , Fatores de Risco , Translocação Genética/genética , Translocação Genética/efeitos da radiação , Ucrânia/epidemiologiaRESUMO
AIM: Although acute myelogenous leukemia (AML) arising after radiation exposure is considered to be secondary, little is known about the molecular mechanisms by which the radiation induces the leukemogenic phenotype. The aim of the study was to analyze whether the MLL translocations are as frequent in radiation-associated AML as in spontaneous AML cases. METHODS: Sixty one AML samples obtained at diagnosis were analyzed for the presence of MLL abnormalities using fluorescent in situ hybridization and/or reverse transcription polymerase chain reaction. Of these patients, 27 had experienced radiation exposure due to the Chernobyl accident, 32 were non-irradiated (spontaneous AML), and 2 developed therapy-related AML after chemotherapy with topoisomerase II inhibitors. RESULTS: MLL gene translocations were detected in both groups of spontaneous and therapy-related AML (1/32 and 1/2 cases respectively). The sole MLL rearrangement found in the group of radiation-associated AML patients was a duplication of the gene. CONCLUSION: Our data preclude the involvement of MLL gene translocations in radiation-induced leukemogenesis, but support the assumption that loss and gain of chromosomal material could be crucial in the leukemogenesis of AML patients with the history of radiation exposure due to the Chernobyl accident.
