RESUMO
The BCL2 breakage mechanism has been shown to be highly dependent on DNA methylation at the major breakpoint region (MBR) CpG sites. We recently described an increased frequency of BCL2/ JH translocation with aging. It is known that methylation levels change with aging. The present study aimed to determine whether methylation alterations at CpG sites of BCL2 MBR were the cause of increased breakages with aging. We analyzed the methylation levels of three CpG sites on the region by pyrosequencing and studied if methylation levels and/or polymorphisms affecting CpG sites were associated with an increase of translocations. We observed that although the methylation levels of MBR CpG sites were higher in individuals with BCL2/JH translocation, in contrast to our expectations, these levels decreased with the age. Moreover, we show that polymorphisms at those CpG sites leading to absence of methylation seem to be a protective factor for the apparition of translocations.
Assuntos
Envelhecimento/genética , Ilhas de CpG/genética , Polimorfismo Genético , Proteínas Proto-Oncogênicas c-bcl-2/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/metabolismo , Criança , Pré-Escolar , Metilação de DNA , Feminino , Frequência do Gene , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Valores de Referência , Estudos Retrospectivos , Translocação Genética , Adulto JovemRESUMO
Chromosome translocations are especially frequent in human lymphomas and leukemias but are insufficient to drive carcinogenesis. Indeed, several of the so-called tumor specific translocations have been detected in peripheral blood of healthy individuals, finding a higher frequency of some of them with aging. The inappropriate repair of DNA double strand breaks by the nonhomologous end joining (NHEJ) pathway is one of the reasons for a translocation to occur. Moreover, fidelity of this pathway has been shown to decline with age. Although the mechanism underlying this inefficacy is unknown, other repair pathways are inactivated by methylation with aging. In this study, we analyzed the implication of NHEJ genes methylation in the increase of translocations with the age. To this aim, we determined the relationship between translocations and aging in 565 Spanish healthy individuals and correlated these data with the methylation status of 11 NHEJ genes. We found higher frequency of BCL2-JH and BCR-ABL (major) translocations with aging. In addition, we detected that two NHEJ genes (LIG4 and XRCC6) presented age-dependent promoter methylation changes. However, we did not observe a correlation between the increase of translocations and methylation, indicating that other molecular mechanisms are involved in the loss of NHEJ fidelity with aging.
Assuntos
Envelhecimento/genética , Reparo do DNA por Junção de Extremidades/genética , Metilação de DNA/genética , Translocação Genética/fisiologia , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/fisiologia , Distribuição de Qui-Quadrado , Criança , Pré-Escolar , Estudos de Coortes , Intervalos de Confiança , Quebras de DNA de Cadeia Dupla , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Razão de Chances , Reação em Cadeia da Polimerase/métodos , Sensibilidade e Especificidade , Transdução de Sinais/genética , Adulto JovemRESUMO
Undiagnosed individuals with celiac disease (CD) or those who do not comply with gluten-free diet (GFD) are at a higher risk of developing malignancies. A possible origin of chromosomal alteration in autoimmune reaction could be mistakes in the rearrangement of V(D)J of the IgH gene. Our aim was to verify whether higher genomic instability was found in coeliac individuals and whether GFD reduced it. As marker of genomic instability we analysed the frequency of 2 translocations, t(14;18) and t(11;14), in peripheral blood by nested PCR, in 37 patients with CD at diagnosis, 27 patients with CD after 2 years on GFD, and 36 control individuals. No significant differences were found.