Kromozom konformasyonu yakalama teknikleriyle 8q24.21 bölgesindeki glioma risk-lokus alanlarının kromatin-kromatin etkileşimlerinin belirlenmesi ve İDH mutasyonunun etkisinin araştırılması

Brain tumors are poorly diagnosed and cause to death of thousands of people around the world every year. Gliomas are the most common brain tumors. Although there have been many mutations associated with gliomas to date, IDH (Isocitrate Dehydrogenase) mutations have been identified as "driver mutations" and are seen in about 80 percent of cases. The number of mutations associated with gliomas has increased day by day. GWAS (Genome Wide Association Studies) has identified significant risk locis and important steps have taken to diagnosis of the disease. The aim of this project is to identify at the molecular level of the mechanism of action of the single nucleotide polymorphism (SNP) rs55705857 G allele,which was found by GWAS, which is located in the 8q24.21 region and is defined as the mostly related glioma allele, and demonstrates its association with the IDH1-R132H mutation. For this purpose, interactions with the risk allele in the immortalized human astrocyte (IHA) cells with and without IDH1-R132H mutation were identified and the candidate interactions that increase the susceptibility to gliomagenesis were determined. In addition, the risk allele was created in the IPSCs (Induced Pluripotent Stem Cells) by genome regulation and increase in the expression of MYC was observed. In addition, expression of MYC has also been found in 2- HG (2-hydroxyglutarate, oncometabolite of IDH-R132H mutations) treated IHA-R132H cells. Our results show that rs55705857 regulates expression of the MYC gene through long-range chromatin-chromatin interactions. The increase of MYC expression due to IDH1-R132H mutation / 2-HG may explain the 8q24-associated glioma risk being specific to IDH-mutant tumors. In conclusion, understanding the mechanism of glioma susceptibility sheds light on the early stages of tumor formation