RESUMEN
B-cell lymphoma 2 (BCL2) and BCL2-associated X protein (BAX) proteins are anti-apoptotic and pro-apoptotic determinants of mitochondrial-mediated apoptosis, and their relative expression determines the cell fate. The promoter polymorphisms in these genes were shown to alter the protein function or expression and exert an impact on apoptosis regulation. Deregulation in the expression of any of these genes leads to disruption of cellular homeostasis and malignant transformation. The present study was aimed to determine the association of BCL2-938C>A and BAX-248G>A promoter polymorphisms with origin and progression of acute myeloid leukemia (AML). We also have performed combined genotype analysis to evaluate the cumulative effect of risk genotypes in the AML development. These polymorphisms were genotyped by polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP) in 221 AML patients and 305 age- and sex-matched healthy controls. Our study revealed that BCL2-938CA (p = 0.018) and BAX-248GG (0.043) genotypes were significantly associated with increased risk for AML occurrence. BAX-248A allele had shown decreased risk for AML. The combined analysis had shown that BCL2-938CA+AA-BAX-248GG group had a 1.63-fold (95 % CI: 1.08-2.45, p = 0.02) increased risk for AML. None of the clinical variables had shown any significant association with both polymorphisms. With respect to complete remission (CR) rate, BAX-248GG genotype (p = 0.002) and G allele (p = 0.009) had conferred significant risk for complete remission failure. Although the log rank test was not significant, survival analysis had shown a trend where BCL2-938CA genotype, and BAX-248GG had reduced median disease-free survival (DFS) of 9 and 10 months, respectively. In conclusion, BCL2-938C>A and BAX-248G>A gene polymorphisms might contribute to the origin of AML. Moreover, influence of BAX-248GG genotype on CR and DFS rate suggests that the BAX-248G>A polymorphism can serve as marker for poor prognosis in AML.
Asunto(s)
Biomarcadores de Tumor/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Polimorfismo de Nucleótido Simple/genética , Regiones Promotoras Genéticas/genética , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteína X Asociada a bcl-2/genética , Adolescente , Adulto , Anciano , Estudios de Casos y Controles , Niño , Preescolar , ADN/análisis , ADN/genética , Femenino , Estudios de Seguimiento , Humanos , India , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , Pronóstico , Tasa de Supervivencia , Adulto JovenRESUMEN
Hypoxia-inducible factor 1α (HIF-1α) is an important transcription factor that regulates different cellular responses to hypoxia. HIF-1α is rapidly degraded by von Hippel-Lindau (VHL) protein under normoxic conditions and stabilized under hypoxia. A common variant of HIF-1α (1772C>T) (rs 11549465) polymorphism, corresponding to an amino acid change from proline to serine at 582 position within the oxygen-dependent degradation domain, results in increased stability of the protein and altered transactivation of its target genes. The present study was aimed to find the association between HIF-1α (1772C>T) (rs 11549465) polymorphism and breast cancer development. For this purpose, 348 primary breast cancer patients and 320 healthy and age-matched controls were genotyped through PCR-RFLP method. The genotype frequencies were compared between patients and controls, and their influence on clinical characteristics of breast cancer patients was analyzed. Our study revealed a significant increase of TT genotype in breast cancer patients compared to controls (p = 0.038). Further, TT genotype and T allele were found to be associated with progesterone receptor (PR)-negative status (p < 0.09). None of the clinical variables revealed significant association with HIF-1α (1772C>T) (rs 11549465) polymorphism.
Asunto(s)
Biomarcadores de Tumor/genética , Neoplasias de la Mama/genética , Carcinoma Ductal de Mama/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Persona de Mediana Edad , Polimorfismo de Longitud del Fragmento de Restricción , Polimorfismo de Nucleótido Simple , Receptores de Progesterona/metabolismo , Adulto JovenRESUMEN
Germline alterations of the TP53 gene encoding the p53 protein have been observed in the majority of families with the Li-Fraumeni syndrome, a rare dominantly inherited disorder with breast cancer. Genomic DNA samples of 182 breast cancer cases and 186 controls were sequenced for TP53 mutations in the exon 5-9 and intervening introns 5, 7-9. Direct sequencing was done using Applied Biosystem 3730 DNA analyzer. In the present study, we observed nine mutations in the sequenced region, of which five were novel. Hardy-Weinberg equilibrium (HWE) was done for all the mutations; C14181T, T14201G, and G13203A have shown deviation from HWE. High linkage disequilibrium (LD) was observed between C14181T (rs129547788) and T14201G (rs12951053) (r (2) = 0.98.3; D' = 1.00), whereas other observed mutations do not show strong LD with any of the other mutations. None of the intronic mutations has shown significant association with the breast cancer, two exonic mutations G13203A (rs28934578) and A14572G are significantly (P = 0.04, P = 0.007) associated with breast cancer. Germline mutations observed in DNA-binding domain of the gene showed significant association with breast cancer. This study reports five novel germline mutations in the TP53 gene out of which one mutation may confer significant risk to the breast cancer. Mutations in DNA-binding domain of TP53 gene may play role in the early onset and prognosis of breast cancer. The population-based studies of germline mutations in DNA-binding domain of TP53 gene helps in identification of individuals and families who are at risk of developing cancers.
Asunto(s)
Neoplasias de la Mama Masculina/genética , Neoplasias de la Mama/genética , Mutación de Línea Germinal , Proteína p53 Supresora de Tumor/genética , Alelos , Secuencia de Bases , Sitios de Unión/genética , ADN/metabolismo , Análisis Mutacional de ADN , Exones/genética , Femenino , Frecuencia de los Genes , Genotipo , Haplotipos , Humanos , Desequilibrio de Ligamiento , Masculino , Modelos Moleculares , Mutación Missense , Polimorfismo de Nucleótido Simple , Conformación Proteica , Factores de Riesgo , Proteína p53 Supresora de Tumor/química , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Multiple myeloma, a clonal plasma cell disorder, commonly affects adults above 50 years age and accounts for about 10% of all hematological malignancies. Anemia, bone pains, renal failure are the most common symptoms at presentation. Though extra-medullary extra-osseous disease is well known in the course of the disease, initial presentation with extramedullary disease alone is rare. Such presentation may represent poor biology of the disease and/or advanced stage. Early diagnosis and treatment may improve outcomes. We herewith report the case of a 43 year old lady who presented with hepatosplenomegaly, without any classical manifestations of multiple myeloma and discuss the relevant literature.
Asunto(s)
Hepatomegalia/etiología , Mieloma Múltiple/complicaciones , Esplenomegalia/etiología , Abdomen/diagnóstico por imagen , Adulto , Antineoplásicos/uso terapéutico , Biopsia , Ácidos Borónicos/uso terapéutico , Bortezomib , Dexametasona/uso terapéutico , Diagnóstico Diferencial , Resultado Fatal , Femenino , Hepatomegalia/terapia , Humanos , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/tratamiento farmacológico , Pirazinas/uso terapéutico , Esplenomegalia/terapia , Tomografía Computarizada por Rayos X , UltrasonografíaRESUMEN
BACKGROUND: Primary central nervous system lymphoma (PCNSL) occurs in both immunocompetent and immunosuppressed individuals. The role of Epstein-Barr virus (EBV) has been implicated in immunosuppressed individuals but its role is not established in immunocompetent individuals. AIMS: To study the possible role of EBV in PCNSL in immunocompetent individuals. SETTING AND DESIGN: Retrospective study. MATERIALS AND METHODS: Thirty patients with PCNSL were studied immunohistochemically with antibodies to CD45, CD20, CD3 and EBV latent membrane protein-1 (EBV LMP-1). In situ hybridization was done in 19 patients where enough tissue was available using a specific oligonucleotide probe for EBV-Early RNA (EBER). RESULTS: All the patients were immunocompetent and mean age was 41.6 years. Histologically they were diffuse large cell lymphoma: 25 (83.3%) were B cell, 1(3.3%) was T cell and 4 (13.3%) were unclassified. EBV LMP-1 showed variable membrane and cytoplasmic positivity in 24 (80%) patients. In situ hybridization for EBER was negative in all the 19 patients studied. CONCLUSION: In this region of the world probably EBV has no etiologic role in PCNSL in immunocompetent individuals.