DNA methylation in the placenta and in cancerwith special reference to folate transporting genes

Detta är en avhandling från Örebro : Örebro university

Sammanfattning: DNA methylation is an epigenetic mechanism that regulates the gene transcription. Folate is used in cellular synthesis of methyl groups, nucleic acids and amino acids. In complex diseases like cancer and neural tube defects (NTD), various genetic and epigenetic alterations can be found that disrupt the normal cell function. The main goals of this thesis were to analyze whether the genes responsible for the folate transport (FOLR1, PCFT, and RFC1) could be regulated by DNA methylation in placenta, blood leukocytes and colorectal cancer. We also addressed the genome-wide DNA methylation changes in colorectal cancer andcervical cancer.We found that changes in the methylated fraction of the RFC1 gene were dependent on the RFC1 80G>A polymorphism in placental specimens with NTDs and blood leukocytes from subjects with high homocysteine (Paper I). In colorectal cancer, the greatest difference in DNA methylation was observed in the RFC1 gene and was related to a lower protein expression (Paper II).In Paper III and IV we studied the DNA methylated fraction using a high-density array. Paper III was focused on genes in the DNA repair pathway and frequently mutated in colorectal cancer. We found that aberrant methylation in the DNA mismatch repair genes was not a frequent event in colorectal cancer and we identified five candidate biomarker genes in colorectal cancer, among them the GPC6 and DCLRE1C genes. In Paper IV, we found hypomethylation of genes involved in the immune system in cervical cancer specimens compared to healthy cervical scrapes and we identified twenty four candidate genes for further evaluation ofclinical value.In conclusion, the work of this thesis filled a relevant knowledge gap regarding the role of differential methylation of the folate transport genes in NTD and colorectal cancer. This thesis work also provided insights into the functional role of DNA methylation in cancer specific pathways and identified potential novel biomarker genes.