New insights into the colorectal carcinogenesis: from early precursor lesions to the role of aneuploidy
[eng] Colorectal cancer (CRC) is one of the most frequent malignancies worldwide and it is considered an important healthcare problem. Moreover, colorectal carcinogenesis is a long stepwise process through a known precursor, the adenoma, providing a perfect scenario for prevention and the identifica...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2017 |
| País: | España |
| Institución: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/120288 |
| Acceso en línea: | https://hdl.handle.net/2445/120288 http://hdl.handle.net/10803/461912 |
| Access Level: | acceso abierto |
| Palabra clave: | Càncer colorectal Marcadors bioquímics Colorectal cancer Biochemical markers |
| Sumario: | [eng] Colorectal cancer (CRC) is one of the most frequent malignancies worldwide and it is considered an important healthcare problem. Moreover, colorectal carcinogenesis is a long stepwise process through a known precursor, the adenoma, providing a perfect scenario for prevention and the identification of biomarkers. In this sense, my thesis dissertation aimed at giving a better understanding of CRC progression by evaluating both early precursor lesions and molecular changes leading to malignant transformation. Aberrant crypt foci (ACF), the earliest visible lesions in the colorectum, and LINE-1 methylation levels have been proposed as predictive biomarkers during CRC development. Nevertheless, their role in the colorectal carcinogenesis is still under debate. A wide cohort of ACF samples and paired normal mucosa extracted from patients at different risk of CRC was used to evaluate the mutational status of CRC key genes, microsatellite instability, and aberrant DNA methylation patterns. As a result, none of the potential biomarkers were found to be suitable to predict CRC development. Understanding the adenoma to adenocarcinoma transition is a decisive step when investigating CRC. In this sense, adenocarcinoma in adenoma samples were used to perform single-cell multi-color FISH in order to assess chromosomal heterogeneity and identify drivers of transition and progression. Interestingly, the gain of chromosomes 7p, 13q and 20q, as well as whole genome duplication, demonstrated to lead CRC evolution. Finally, the effects of whole genome duplication on cellular behavior were evaluated for two CRC cell lines, DLD-1 and RKO. Transcriptomic profiling revealed the dysregulation of genes related with replication in tetraploid cancer cells. Moreover, these cells showed replication stress, which triggered genomic instability and chromosome aberrations. Furthermore, polyploidization was found to be associated with an increased capacity for mobility, which explained the presence of tetraploid cells in the invasive fronts of colon adenocarcinomas. |
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