RESUMO
Epstein-Barr virus (EBV) is an important environmental factor associated to the development of Burkitt lymphoma (BL) in endemic and intermediate risk regions. However, little is known about the contribution of genetic constitution to the development and clinical response of the disease. The aim of this work was to investigate the role of EBV and Interleukin 10 (IL10) single nucleotide polymorphisms (-1082A/G, -819C/T, -592C/A) and microsatellites (IL10.R and IL10.G) in susceptibility and clinical outcome in pediatric BL patients, in a region with intermediate EBV association frequency. The frequencies of IL10 promoter Single nucleotide polymorphisms -1082A/G, -819C/T, -592C/A, and IL10.R and IL10.G microsatellites were compared in 62 pediatric patients and 216 healthy donors. IL10 -1082GG and GCC/GCC genotypes were more frequent in patients than in controls, and associated to a higher risk of BL development (GG genotype OR 2.62, 95% CI, 1.25-5.51; P = 0.008; Pc = 0.024). EBV was detected in tumor samples by EBER-ISH in 54.1% of cases. EBV+ patients exhibited a better event free survival (EFS) (P = 0.019) than EBV- patients. Carriers of IL10 R3-GCC had worse EFS (P = 0.028). Our results suggest a risk effect and an independent prognostic value of IL10 polymorphisms and EBV in childhood BL patients.
Assuntos
Linfoma de Burkitt/genética , Linfoma de Burkitt/virologia , Herpesvirus Humano 4/isolamento & purificação , Interleucina-10/genética , Adolescente , Linfoma de Burkitt/diagnóstico , Linfoma de Burkitt/etiologia , Criança , Pré-Escolar , Intervalo Livre de Doença , Infecções por Vírus Epstein-Barr/complicações , Feminino , Frequência do Gene , Genótipo , Humanos , Lactente , Masculino , Repetições de Microssatélites , Polimorfismo de Nucleotídeo Único , Prognóstico , Regiões Promotoras Genéticas , Fatores de RiscoRESUMO
Hodgkin lymphoma (HL) shows a bimodal distribution with a first peak in developing countries during childhood. The causative role and prognostic significance of Epstein-Barr virus (EBV) association in patients with HL is controversial. Our aim was to perform a comparative study of EBV association in 2 Latin American pediatric HL series, and to correlate it with patient's survival. Epstein-Barr encoded RNAs in situ hybridization and latent membrane protein 1 immunohistochemistry were performed on formalin-fixed, paraffin-embedded HL biopsies from 176 pediatric patients from 2 public institutions from Argentina and Southeast Brazil. Mixed cellularity subtype was prevalent in Argentine HL (Arg HL) (52%) and nodular sclerosis subtype in Brazilian HL (BR HL) (83%). EBV expression was detected in 52% of cases, namely 54% Arg HL and 48% Br HL. EBV was significantly associated with mixed cellularity subtype in both populations. In Arg HL, EBV positivity was significantly higher in patientsAssuntos
Infecções por Vírus Epstein-Barr/epidemiologia
, Doença de Hodgkin/epidemiologia
, Adolescente
, Argentina/epidemiologia
, Biópsia
, Brasil/epidemiologia
, Criança
, Pré-Escolar
, Infecções por Vírus Epstein-Barr/complicações
, Feminino
, Doença de Hodgkin/classificação
, Doença de Hodgkin/complicações
, Doença de Hodgkin/mortalidade
, Doença de Hodgkin/patologia
, Humanos
, Masculino
, Estadiamento de Neoplasias
, Análise de Sobrevida
, Resultado do Tratamento
RESUMO
Epstein-Barr virus (EBV) is implicated in the pathogenesis of several lymphoid and epithelial neoplasms. Latent membrane protein 1 (LMP1) is the major viral oncogene and it is controversial whether tumor LMP1 variants reflect their geographical predominance or are associated with enhanced oncogenic properties. This study aimed to analyze LMP1 molecular variability of 62 EBV+ Hodgkin's lymphomas and 22 non-neoplastic controls from Brazil and Argentina. EBV association was characterized by EBER-ISH, LMP1 immunohistochemistry and PCR assays for EBNA2 and 3C (typing), LMP1 30 bp deletion (del30) and number of 33 bp tandem repeats. LMP1 C-terminal sequencing was performed in 42 cases. EBV1 was the predominant strain in both geographical Hodgkin's lymphoma groups (average 82%). A higher frequency of del30 variant was observed in lymphomas (41/63) than in non-neoplastic controls (6/22) (OR 4.97, CI 95% 1.53-16.79; P = 0.005, chi(2) test). A large number (5-7) of 33 bp repeat units was characteristic of del30 LMP1 variants (P < 0.0001, Fisher's exact test). Sequence analysis showed a similar mutation spectrum to that described worldwide but none of the current classification schemes could be applied completely. A distinct structural pattern was observed in del30 variants, characterized by a large number of 33 bp repeat units and the presence of a 15 bp insertion encoding the JAK3 Box-1a motif (3/15 wt vs. 16/20 del30; P = 0.001, chi(2) test). The results suggest a pathogenic role for LMP1 del30 variants in Hodgkin's lymphoma from South America and point to particular virus-host molecular mechanisms, such as genomic instability in LMP1 carboxy-terminus, leading to enhanced production and selection of these deletion variants.
Assuntos
Variação Genética , Herpesvirus Humano 4/patogenicidade , Doença de Hodgkin/virologia , Proteínas da Matriz Viral/química , Proteínas da Matriz Viral/genética , Sequência de Aminoácidos , Argentina , Brasil , Herpesvirus Humano 4/classificação , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/isolamento & purificação , Humanos , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , Análise de Sequência de DNA , Deleção de SequênciaRESUMO
BACKGROUND: To evaluate the importance of timing of radiation therapy in children with PNET/medulloblastoma, treated at the Brazilian National Cancer Institute (INCA). PROCEDURE: The records of 101 children with confirmed diagnosis of medulloblastoma were retrospectively reviewed. Patients had a median follow-up of 48 months (0.5-241 months). The age varied from 0.8 to 17.5 years (median: 7.6 years) and 21.7% were 3 years old or younger. RESULTS: According to the data collected from patients that received treatment for medulloblastoma from 1983 to 2001, the overall survival (OS) rate was 53% and the Disease Free Survival (DFS) rate was 40%. Multivariate analysis showed that under age 3 years, presence of neoplasic cells in the cerebrospinal fluid (CSF) at presentation or subtotal tumor resection resulted in a worse OS. The patients that received a biological effective dose (BED) greater than 44 Gy10 had better prognosis. Two-thirds of the patients had complete response after the initial treatment. Among them, 50% (34 patients) recurred, and of those 34 patients, 42% of them (14 patients) had recurrence in the posterior fossa. CONCLUSION: Surgery with total resection of the tumor and absence of neoplasic cells in the CSF are effective predictors of better OS. Radiotherapy was more effective when a BED was greater than 44 Gy10.