Cancer usually arises through mutational changes in the genome but also epigenetic changes can contribute to tumorigenesis. In this research we studied both sporadically occurring and familial colorectal, endometrial and gastric tumors. Sporadic tumors were divided into separate categories depending on the microsatellite instability status of the tumor. In addition to sporadic tumors we studied tumors from patients with different cancer syndromes: Lynch syndrome, Familial colorectal cancer type X and Familial site-specific endometrial cancer. Lynch syndrome patients have a predisposing germline mutation in one of the mismatch repair genes (MLH1, MSH2 or MSH6) and the tumors are typically microsatellite unstable. Despite the extensive research efforts, the genetic or epigenetic background of the other studied syndromes is not known and remains to be molecularly characterized. We therefore explored the possible epigenetic basis of cancer susceptibility in these syndromes. First we studied the promoter methylation of 24 established tumor suppressor genes. Hypermethylation patterns were found to be characteristic of each tissue and diversely dependent on the microsatellite instability status of the tumor, or family category. The CpG island methylator phenotype (CIMP) in which multiple loci are silenced by promoter methylation, was most evident in sporadic microsatellite unstable tumors (P less than 0.001) and was present in 38% of all of the studied colorectal, 19% of endometrial and 29% of gastric tumors. In these tumors the CIMP phenotype can contribute to the genomic instability and the progression of cancer. In addition, despite being microsatellite stable, 50% of Familial colorectal cancer type X tumors displayed the CIMP phenotype. Our results of global hypomethylation confirm that tumors have significantly lower methylation levels compared to normal tissues in most of the studied patient groups (P less than 0.05) and that the hypomethylation levels depend significantly on the microsatellite instability status of the tumors (P = 0.042 for colorectal and P = 0.018 for gastric tumors). The significant decrease in the methylation levels, observed especially in the normal tissues of Familial colorectal cancer type X patients, could function as a premalignant field defect, where a large area of tissue is affected by carcinogenic alteration, and hence promote cancer development by facilitating the accumulation of other lesions such as genetic mutations or other epigenetic changes in the affected areas. After the characterization of different DNA methylation aberrations in distinct tumor categories, we studied the possible mechanisms behind the observed methylation changes. We evaluated the association of the expression of DNA methyltransferases DNMT1 and DNMT3B and histone methyltransferase EZH2 with CIMP+ phenotype and global hypomethylation patterns. Compared to the normal tissues, all the studied methyltransferases were significantly overexpressed in colorectal tumors (P less than 0.001) and DNMT3B also in endometrial tumors (P less than 0.001). EZH2 overexpression was shown to associate with CIMP+ phenotype especially in sporadic colorectal tumors and the finding was statistically significant (P = 0.003). The overall aim of this research was to elucidate epigenetic mechanisms in cancer, including cancers of different organs and also different familial cancers. Available information on the epigenetic events of cancers is increasing and although the topic is under continuous study, our understanding of it is still limited. New knowledge in the field can increase the understanding of the basic tumorigenic mechanisms and thereby facilitate more specific and earlier diagnosis and treatment of different types of cancer. Also the potential reversibility of epigenetic states offers interesting possibilities for drug development.
|Status||Publicerad - 2015|
|MoE-publikationstyp||G5 Doktorsavhandling (artikel)|
- 3111 Biomedicinska vetenskaper