Genetic and epigenetic insights into colorectal tumorigenesis

Programa de Doctorat en Biomedicina / Tesi realitzada a l'Institut de Recerca Germans Trias i Pujol (IGTP)

Detalles Bibliográficos
Autor: Matas Gironella, Júlia
Tipo de recurso: tesis doctoral
Estado:Versión publicada
Fecha de publicación:2021
País:España
Institución:CBUC, CESCA
Repositorio:TDR. Tesis Doctorales en Red
OAI Identifier:oai:www.tdx.cat:10803/674374
Acceso en línea:http://hdl.handle.net/10803/674374
Access Level:acceso abierto
Palabra clave:Càncer colorectal
Cáncer colorrectal
Colorectal cancer
Metilació
Metilación
Methylation
ADN
DNA
Còlon
Colon
Ciències Experimentals i Matemàtiques
616
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oai_identifier_str oai:www.tdx.cat:10803/674374
network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv Genetic and epigenetic insights into colorectal tumorigenesis
title Genetic and epigenetic insights into colorectal tumorigenesis
spellingShingle Genetic and epigenetic insights into colorectal tumorigenesis
Matas Gironella, Júlia
Càncer colorectal
Cáncer colorrectal
Colorectal cancer
Metilació
Metilación
Methylation
ADN
DNA
Còlon
Colon
Ciències Experimentals i Matemàtiques
616
title_short Genetic and epigenetic insights into colorectal tumorigenesis
title_full Genetic and epigenetic insights into colorectal tumorigenesis
title_fullStr Genetic and epigenetic insights into colorectal tumorigenesis
title_full_unstemmed Genetic and epigenetic insights into colorectal tumorigenesis
title_sort Genetic and epigenetic insights into colorectal tumorigenesis
dc.creator.none.fl_str_mv Matas Gironella, Júlia
author Matas Gironella, Júlia
author_facet Matas Gironella, Júlia
author_role author
dc.contributor.none.fl_str_mv Peinado Morales, Miguel Á. (Miguel Ángel)
Corominas, Montserrat (Corominas Guiu)
Universitat de Barcelona. Facultat de Biologia
dc.subject.none.fl_str_mv Càncer colorectal
Cáncer colorrectal
Colorectal cancer
Metilació
Metilación
Methylation
ADN
DNA
Còlon
Colon
Ciències Experimentals i Matemàtiques
616
topic Càncer colorectal
Cáncer colorrectal
Colorectal cancer
Metilació
Metilación
Methylation
ADN
DNA
Còlon
Colon
Ciències Experimentals i Matemàtiques
616
description Programa de Doctorat en Biomedicina / Tesi realitzada a l'Institut de Recerca Germans Trias i Pujol (IGTP)
publishDate 2021
dc.date.none.fl_str_mv 2021
2022
2022
dc.type.none.fl_str_mv info:eu-repo/semantics/doctoralThesis
info:eu-repo/semantics/publishedVersion
format doctoralThesis
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10803/674374
url http://hdl.handle.net/10803/674374
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 190 p.
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Universitat de Barcelona
publisher.none.fl_str_mv Universitat de Barcelona
dc.source.none.fl_str_mv TDX (Tesis Doctorals en Xarxa)
reponame:TDR. Tesis Doctorales en Red
instname:CBUC, CESCA
instname_str CBUC, CESCA
reponame_str TDR. Tesis Doctorales en Red
collection TDR. Tesis Doctorales en Red
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869405654593044480
spelling Genetic and epigenetic insights into colorectal tumorigenesisMatas Gironella, JúliaCàncer colorectalCáncer colorrectalColorectal cancerMetilacióMetilaciónMethylationADNDNACòlonColonCiències Experimentals i Matemàtiques616Programa de Doctorat en Biomedicina / Tesi realitzada a l'Institut de Recerca Germans Trias i Pujol (IGTP)Colorectal cancer (CRC) is a major health burden with large numbers of new cases worldwide and high disease-specific mortality, despite great advances made towards improving patient clinical outcomes. It arises through the gradual acquisition of particular genetic and epigenetic alterations within normal cells, giving them selective advantage in driving malignant transformation. As such process takes over a decade, early cancer detection actions should strongly impact reducing morbidity. Identification of reliable CRC biomarkers is a permanent challenge for improving CRC management. Thanks to the emergence of new powerful technologies and the advances in the knowledge of the mechanistic bases of the disease, recent genetic and epigenetic markers are becoming promising candidates for early detection, risk stratification, prognosis, and prediction of treatment response. In this doctoral thesis, we have addressed mechanistic and clinical aspects of colorectal tumorigenesis: the deregulation and function of FOXD2 and FOXD2- AS1 in CRC tissues and cell lines (study I) and the role of precancerous mutations in normal colorectal mucosa (study II). In study I, we characterized the transcriptomic and epigenetic profiles of FOXD2 and FOXD2-AS1 genes in normal and tumor colorectal samples. As bidirectional genes in head- to-head disposition, they showed a strong correlation at the transcriptomic level. However, in tumors they displayed an unbalanced bidirectional expression, whereas FOXD2 was strongly downregulated in association with higher methylation levels outside the promoter region. Interestingly, when we induced overexpression of such genes in CRC cell lines, FOXD2 behaved as a tumor suppressor by reducing migration and colony formation, while FOXD2-AS1 increased migration rates. Overall, our findings suggest the involvement of major mechanisms rewiring cancer, responsible for an altered bidirectional transcription of FOXD2 and FOXD2-AS1. In study II, we focused on the characterization of somatic mutation in normal colorectal mucosa of individuals with and without CRC, using an ultra-deep sequencing technology, CRISPR-Duplex Sequencing. We identified coding mutations in normal colon of most individuals on the 4 cancer genes included in the panel: BRAF, KRAS, PIK3CA, and TP53. However, TP53 and KRAS driver mutations were commonly found in normal colon of CRC patients, often displaying clonal expansions in early onset CRC. Additionally, we developed a primary and integrative mutational model based on the mutational analysis of normal biopsies with potential for CRC risk prediction. Overall, our results support a model where somatic evolution contributes to the expansion of mutated clones in the normal colon tissue, but this process is enhanced in young individuals with cancer.Universitat de BarcelonaPeinado Morales, Miguel Á. (Miguel Ángel)Corominas, Montserrat (Corominas Guiu)Universitat de Barcelona. Facultat de Biologia202220222021info:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/publishedVersion190 p.application/pdfapplication/pdfhttp://hdl.handle.net/10803/674374TDX (Tesis Doctorals en Xarxa)reponame:TDR. Tesis Doctorales en Redinstname:CBUC, CESCAInglésADVERTIMENT. Tots els drets reservats. L'accés als continguts d'aquesta tesi doctoral i la seva utilització ha de respectar els drets de la persona autora. Pot ser utilitzada per a consulta o estudi personal, així com en activitats o materials d'investigació i docència en els termes establerts a l'art. 32 del Text Refós de la Llei de Propietat Intel·lectual (RDL 1/1996). Per altres utilitzacions es requereix l'autorització prèvia i expressa de la persona autora. En qualsevol cas, en la utilització dels seus continguts caldrà indicar de forma clara el nom i cognoms de la persona autora i el títol de la tesi doctoral. No s'autoritza la seva reproducció o altres formes d'explotació efectuades amb finalitats de lucre ni la seva comunicació pública des d'un lloc aliè al servei TDX. Tampoc s'autoritza la presentació del seu contingut en una finestra o marc aliè a TDX (framing). Aquesta reserva de drets afecta tant als continguts de la tesi com als seus resums i índexs.info:eu-repo/semantics/openAccessoai:www.tdx.cat:10803/6743742026-06-14T12:46:07Z
score 15,300724

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