Genomic determinants of chronic lymphocytic leukemia progression: from individual drivers to a heterogeneous genetic makeup

[eng] Chronic lymphocytic leukemia (CLL) is the most common form of adult leukemia in Western countries. Although the disease might follow an indolent course, it rapidly progresses in a fraction of cases, become resistant to treatment, and eventually transform to a more aggressive B-cell lymphoma, k...

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Detalhes bibliográficos
Autor: Nadeu Prat, Ferran
Formato: tesis doctoral
Estado:Versión publicada
Fecha de publicación:2020
País:España
Recursos:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/171259
Acesso em linha:https://hdl.handle.net/2445/171259
http://hdl.handle.net/10803/669770
Access Level:acceso abierto
Palavra-chave:Ciències de la salut
Bioinformàtica
Genòmica
Càncer
Leucèmia limfocítica crònica
Medical sciences
Bioinformatics
Genomics
Cancer
Chronic lymphocytic leukemia
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oai_identifier_str oai:diposit.ub.edu:2445/171259
network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv Genomic determinants of chronic lymphocytic leukemia progression: from individual drivers to a heterogeneous genetic makeup
title Genomic determinants of chronic lymphocytic leukemia progression: from individual drivers to a heterogeneous genetic makeup
spellingShingle Genomic determinants of chronic lymphocytic leukemia progression: from individual drivers to a heterogeneous genetic makeup
Nadeu Prat, Ferran
Ciències de la salut
Bioinformàtica
Genòmica
Càncer
Leucèmia limfocítica crònica
Medical sciences
Bioinformatics
Genomics
Cancer
Chronic lymphocytic leukemia
title_short Genomic determinants of chronic lymphocytic leukemia progression: from individual drivers to a heterogeneous genetic makeup
title_full Genomic determinants of chronic lymphocytic leukemia progression: from individual drivers to a heterogeneous genetic makeup
title_fullStr Genomic determinants of chronic lymphocytic leukemia progression: from individual drivers to a heterogeneous genetic makeup
title_full_unstemmed Genomic determinants of chronic lymphocytic leukemia progression: from individual drivers to a heterogeneous genetic makeup
title_sort Genomic determinants of chronic lymphocytic leukemia progression: from individual drivers to a heterogeneous genetic makeup
dc.creator.none.fl_str_mv Nadeu Prat, Ferran
author Nadeu Prat, Ferran
author_facet Nadeu Prat, Ferran
author_role author
dc.contributor.none.fl_str_mv Campo Güerri, Elias
Universitat de Barcelona. Facultat de Medicina
dc.subject.none.fl_str_mv Ciències de la salut
Bioinformàtica
Genòmica
Càncer
Leucèmia limfocítica crònica
Medical sciences
Bioinformatics
Genomics
Cancer
Chronic lymphocytic leukemia
topic Ciències de la salut
Bioinformàtica
Genòmica
Càncer
Leucèmia limfocítica crònica
Medical sciences
Bioinformatics
Genomics
Cancer
Chronic lymphocytic leukemia
description [eng] Chronic lymphocytic leukemia (CLL) is the most common form of adult leukemia in Western countries. Although the disease might follow an indolent course, it rapidly progresses in a fraction of cases, become resistant to treatment, and eventually transform to a more aggressive B-cell lymphoma, known as Richter syndrome. The mechanisms underlying these distinct clinical courses are not fully understood. In this Thesis, we aimed to elucidate the genomic determinants of CLL progression, to provide tools to characterize these tumors from next-generation sequencing data, and to extract key biological findings that could improve the management of the patients. In the first chapter (Studies 1 and 2), we characterized a noncoding mutation effecting the small nuclear RNA U1, a component of the spliceosome involved in the 5’ splice site recognition via base paring. Mutations in this gene altered the splicing and expression of multiple genes, were found in CLL tumors lacking clinically relevant genomic alterations, and were independently associated with patients’ outcome. In the next chapter (Studies 3, 4, and 5), we aimed to deeper into the subclonal architecture of CLL. We identified mutations present in small subpopulations associated with disease progression, recognized common evolutionary trajectories, and showed that the integration of the whole tumor architecture into prognostic models could improve the stratification of the patients. In the third chapter (Study 6), we analyzed the whole genome of CLL patients undergoing Richter syndrome and observed that this transformation was accompanied by an increased mutational and genomic complexity. We identified a unifying mutational process that could orchestrate this genomic chaos. In the fourth chapter (Studies 7 and 8), we developed a bioinformatic algorithm aimed to reconstruct the immunoglobulin gene rearrangements in lymphoid neoplasms from whole-genome sequencing, which might facilitate the use of this methodology in the future clinical practice. By applying this algorithm, we studied a recurrent mutation in the IGLV3-21 gene associated with an aggressive disease with a strong influence on the current and future risk stratification of CLL patients. Altogether, this Thesis has contributed to understand the genomic determinants of CLL progression through the analysis of its dynamic and heterogeneous genetic makeup.
publishDate 2020
dc.date.none.fl_str_mv 2020
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 https://hdl.handle.net/2445/171259
http://hdl.handle.net/10803/669770
url https://hdl.handle.net/2445/171259
http://hdl.handle.net/10803/669770
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv (c) Nadeu Prat, Ferran, 2020
info:eu-repo/semantics/openAccess
rights_invalid_str_mv (c) Nadeu Prat, Ferran, 2020
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 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 Tesis Doctorals - Facultat - Medicina
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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spelling Genomic determinants of chronic lymphocytic leukemia progression: from individual drivers to a heterogeneous genetic makeupNadeu Prat, FerranCiències de la salutBioinformàticaGenòmicaCàncerLeucèmia limfocítica crònicaMedical sciencesBioinformaticsGenomicsCancerChronic lymphocytic leukemia[eng] Chronic lymphocytic leukemia (CLL) is the most common form of adult leukemia in Western countries. Although the disease might follow an indolent course, it rapidly progresses in a fraction of cases, become resistant to treatment, and eventually transform to a more aggressive B-cell lymphoma, known as Richter syndrome. The mechanisms underlying these distinct clinical courses are not fully understood. In this Thesis, we aimed to elucidate the genomic determinants of CLL progression, to provide tools to characterize these tumors from next-generation sequencing data, and to extract key biological findings that could improve the management of the patients. In the first chapter (Studies 1 and 2), we characterized a noncoding mutation effecting the small nuclear RNA U1, a component of the spliceosome involved in the 5’ splice site recognition via base paring. Mutations in this gene altered the splicing and expression of multiple genes, were found in CLL tumors lacking clinically relevant genomic alterations, and were independently associated with patients’ outcome. In the next chapter (Studies 3, 4, and 5), we aimed to deeper into the subclonal architecture of CLL. We identified mutations present in small subpopulations associated with disease progression, recognized common evolutionary trajectories, and showed that the integration of the whole tumor architecture into prognostic models could improve the stratification of the patients. In the third chapter (Study 6), we analyzed the whole genome of CLL patients undergoing Richter syndrome and observed that this transformation was accompanied by an increased mutational and genomic complexity. We identified a unifying mutational process that could orchestrate this genomic chaos. In the fourth chapter (Studies 7 and 8), we developed a bioinformatic algorithm aimed to reconstruct the immunoglobulin gene rearrangements in lymphoid neoplasms from whole-genome sequencing, which might facilitate the use of this methodology in the future clinical practice. By applying this algorithm, we studied a recurrent mutation in the IGLV3-21 gene associated with an aggressive disease with a strong influence on the current and future risk stratification of CLL patients. Altogether, this Thesis has contributed to understand the genomic determinants of CLL progression through the analysis of its dynamic and heterogeneous genetic makeup.[cat] La leucèmia limfocítica crònica (LLC) és la forma més freqüent de leucèmia en adults als països occidentals. Malgrat que la malaltia pot seguir un curs clínic indolent, aquesta pot progressar ràpidament en una fracció dels casos, tornant-se resistent al tractament i, fins i tot, transformar a un limfoma de cèl·lules B més agressiu, fenomen conegut com síndrome de Richter. Els mecanismes que condicionen aquests diferents cursos clínics no són del tot coneguts. Els objectius d’aquesta tesi doctoral van ser elucidar els determinants genòmics de la progressió de la LLC, proporcionar eines per caracteritzar aquests tumors a partir de dades de seqüenciació de nova generació i extreure aspectes biològics clau d’aquests tumors que permetin millorar el maneig dels pacients. Al primer capítol (estudis 1 i 2), vam caracteritzar una mutació no codificant que afectava l’ARN nuclear petit U1, un component de l’espliceosoma implicat en el reconeixement del lloc 5’ d’empalmament (o splicing) per complementarietat de seqüència. Les mutacions d’aquest gen van alterar l’splicing i l’expressió de múltiples gens, es van trobar en tumors de LLC mancats d’alteracions genòmiques clínicament rellevants i es van associar de forma independentment amb el pronòstic dels pacients. En el següent capítol (estudis 3, 4 i 5), vam intentar aprofundir en l’arquitectura subclonal de la LLC. Es van identificar mutacions presents en petites subpoblacions associades a la progressió de la malaltia, es van reconèixer trajectòries evolutives comunes i es va demostrar que la integració de l'arquitectura tumoral en models pronòstics podria millorar l'estratificació dels pacients. En el tercer capítol (estudi 6), vam analitzar el genoma complet de pacients amb LLC que desenvolupaven la síndrome de Richter i vam observar que aquesta transformació anava acompanyava d’un augment de la complexitat mutacional i genòmica. Vam identificar un procés mutacional unificador que podria orquestrar aquest caos genòmic. Al quart capítol (estudis 7 i 8), vam desenvolupar un algoritme bioinformàtic dirigit a reconstruir els reordenaments genètics de les immunoglobulines en les neoplàsies limfoides a partir de la seqüenciació del genoma complet, cosa que podria facilitar l’ús d’aquesta metodologia en la pràctica clínica. Mitjançant l’aplicació d’aquest algoritme, vam estudiar una mutació recurrent en el gen IGLV3-21 associada a una malaltia agressiva amb una forta influència en la present i futura estratificació dels pacients amb LLC. En conjunt, aquesta tesi ha contribuït a entendre els determinants genòmics de la progressió de la LLC mitjançant l’anàlisi de la seva dinàmica i heterogènia composició genètica.Universitat de BarcelonaCampo Güerri, EliasUniversitat de Barcelona. Facultat de Medicina2020info:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/171259http://hdl.handle.net/10803/669770Tesis Doctorals - Facultat - Medicinareponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglés(c) Nadeu Prat, Ferran, 2020info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1712592026-05-27T06:46:51Z
score 15.301603

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