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Please use this identifier to cite or link to this item: http://hdl.handle.net/10277/838

Authors: Trapani, Davide
Internal Tutor: FURLAN, DANIELA
Title: DNA hypomethylation and hypermethylation in colorectal cancer initiation.
Abstract: This project was focused on identification of new valuable molecular risk factors for the onset of colorectal cancer (CRC), studying both KRAS/NRAS/BRAF/PIK3CA mutations and DNA global hypomethylation in the early events of colorectal carcinogenesis. We analyzed a cohort of 52 colorectal adenomas and 11 carcinomas derived from MAP subjects, 80 sporadic adenomas and 15 carcinomas and a control set of 36 FAP/AFAP adenomas. Moreover, we characterized the L1-MET transcript induced by L1 hypomethylation. We observed that the early steps of oxidative DNA damage in MAP carcinogenesis are characterized by a specific pattern of somatic mutations. We also found that MAP adenomas and carcinomas show a decreased DNA global methylation and specific L1-MET hypomethylation. Finally, we hypothesized that DNA hypomethylation and expression of L1-MET chimeric transcript may play an early role in colorectal carcinogenesis characterizing a subset of more aggressive precursor lesions and cancers. In the second part of the thesis, we studied the promoter of MutL homolog 1 (MLH1) in order to elucidate the relationship between methylation and risk/protective allele at rs1800734 during CRC progression. We confirmed the association of rs1800734 with microsatellite instability (MSI) in our own data. In 33 normal colon biopsies, small allele-specific differences exist only in methylation, but not gene expression. In contrast, allele-specific differences in both MLH1 methylation and expression are present in 35 MSI cancers. We showed that MLH1 transcriptional repression is dependent on DNA methylation and can be reversed by a methylation inhibitor. The rs1800734 allele influences the rate of methylation loss and amount of re-expression.
Keywords: Colorectal cancer, preneoplastic lesions, DNA hypomethylation, rs1800734, MLH1 expressin and promoter methylation
Issue Date: 2019
Language: eng
Doctoral course: Medicina sperimentale e traslazionale
Academic cycle: 30
Publisher: Università degli Studi dell'Insubria
Citation: Trapani, D.DNA hypomethylation and hypermethylation in colorectal cancer initiation. (Doctoral Thesis, Università degli Studi dell'Insubria, 2019).

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