The role of genomic DNA methylation in the risk and progression of urothelial carcinoma of the bladder

• Autores: Salman Muhammad Tajuddin
• Directores de la Tesis: Núria Malats Riera (dir. tes.), Andre Filipe Santos Amaral (dir. tes.)
• Lectura: En la Universidad Autónoma de Madrid ( España ) en 2013
• Idioma: inglés
• Tribunal Calificador de la Tesis: Fernando Rodríguez Artalejo (presid.), Mario Fernández Fraga (secret.), Mariangela Mancini (voc.), Yves Allory (voc.), Víctor Moreno Aguado (voc.)
• Materias:
  • Ciencias médicas
    • Patología
      • Oncología
• Enlaces
  • Tesis en acceso abierto en: Biblos-e Archivo
• Resumen

  • Urothelial carcinoma of the bladder (UCB) is one of the most common cancer types in the developed world, especially in men. Established risk factors for UCB are tobacco smoking, occupational and exposure to aromatic amines, and environmental exposure to arsenic. Recently, 12 genetic variants have been reported to be associated with UCB, among them those in NAT2 and GSTM1; these genes modify the risk conferred by smoking. DNA methylation plays an important role in cellular differentiation and growth, and altered methylation levels in cancer tissues are a hallmark of the disease. Both regional and global DNA methylation changes have been observed in UCB tissue. DNA methylation levels may be influenced by genetic and environmental factors but are poorly characterized. Thus, the objectives of this thesis are to identify predictors of genomic DNA methylation measured at LINE-1 and D4Z4 repeat sequences in granulocyte DNA; to investigate the association between genomic DNA methylation and the risk and progression of UCB, and; to identify modifiers of these associations.

    In this thesis, methylation levels in bisulfite-treated granulocyte DNA were determined by pyrosequencing at LINE-1 (952 cases and 892 controls) and D4Z4 (707 cases and 718 controls) repeats from subjects of the Spanish Bladder Cancer/EPICURO Study. Data on sociodemographic characteristics, smoking, trace elements, single nucleotide polymorphisms (SNPs) in 24 one-carbon metabolism pathway genes, clinicopathological, and follow-up data was considered in the analyses. Multivariable robust linear regression, logistic regression and Cox proportional hazards regression were used to identify potential predictors of genomic DNA methylation, assess its association with risk, and determine its prognostic potential in UCB, respectively. Likelihood ratio test was used to compare the models with and without the multiplicative interaction term and estimate the interaction p-value.

    LINE-1 methylation levels were associated with sex, tobacco type, arsenic, iron, and nickel, and seven genetic variants in one-carbon metabolism pathway genes (DNMT3Ars7581217, AS3MT-rs7085104, MTHFS-rs1380642, SLC19A1-rs914238, and rs9621049, rs9606756, rs4820887 in TCN2). D4Z4 methylation levels were associated with sex, tobacco type, and selenium. LINE-1 methylation showed a U-shaped association with risk of UCB. Both the lowest and highest tertiles were associated with increased risk of UCB when compared to the middle tertile. This association was modified by five SNPs in the PEMT gene. Individuals with 8 D4Z4 methylation levels above or equal to the median had a slightly increased risk of UCB.

    D4Z4 hypermethylation was associated with significantly increased risk of low-grade nonmuscle- invasive bladder cancer overexpressing FGFR3. The overall risk conferred by D4Z4 hypermethylation was significantly modified by iron, manganese, and zinc, and FOLH1- rs11040387. LINE-1 methylation and D4Z4 methylation levels were not associated with individual outcomes of UCB.

    In summary, personal characteristics, environmental factors and common genetic polymorphisms in one-carbon metabolism pathway genes were associated with genomic DNA methylation. Genomic DNA methylation was associated with increased risk of UCB, and this risk was modified by trace elements and genetic polymorphisms. These results show the potential of genomic DNA methylation as a biomarker of susceptibility to UCB. Further studies in larger populations are required to confirm these findings.