Genetic predisposition to radiotherapy-induced toxicity
Programa de Doctorat en Biomedicina / Tesi realitzada a l'Institut d'Oncologia Vall d’Hebron (VHIO)
| Autor: | |
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2024 |
| País: | España |
| Institución: | CBUC, CESCA |
| Repositorio: | TDR. Tesis Doctorales en Red |
| OAI Identifier: | oai:www.tdx.cat:10803/691409 |
| Acceso en línea: | http://hdl.handle.net/10803/691409 |
| Access Level: | acceso abierto |
| Palabra clave: | Oncologia Oncología Oncology Radioteràpia Radioterapia Radiotherapy Genètica mèdica Genética médica Medical genetics Efectes secundaris Efectos secundarios Side effects Micro RNAs MicroRNAs Ciències de la Salut 616 |
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oai:www.tdx.cat:10803/691409 |
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España |
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| dc.title.none.fl_str_mv |
Genetic predisposition to radiotherapy-induced toxicity |
| title |
Genetic predisposition to radiotherapy-induced toxicity |
| spellingShingle |
Genetic predisposition to radiotherapy-induced toxicity Aguado Flor, Ester Oncologia Oncología Oncology Radioteràpia Radioterapia Radiotherapy Genètica mèdica Genética médica Medical genetics Efectes secundaris Efectos secundarios Side effects Micro RNAs MicroRNAs Ciències de la Salut 616 |
| title_short |
Genetic predisposition to radiotherapy-induced toxicity |
| title_full |
Genetic predisposition to radiotherapy-induced toxicity |
| title_fullStr |
Genetic predisposition to radiotherapy-induced toxicity |
| title_full_unstemmed |
Genetic predisposition to radiotherapy-induced toxicity |
| title_sort |
Genetic predisposition to radiotherapy-induced toxicity |
| dc.creator.none.fl_str_mv |
Aguado Flor, Ester |
| author |
Aguado Flor, Ester |
| author_facet |
Aguado Flor, Ester |
| author_role |
author |
| dc.contributor.none.fl_str_mv |
Gutiérrez Enríquez, Sara Giralt López de Sagredo, Jordi Sànchez, Àlex (Sànchez Pla) Universitat de Barcelona. Facultat de Biologia |
| dc.subject.none.fl_str_mv |
Oncologia Oncología Oncology Radioteràpia Radioterapia Radiotherapy Genètica mèdica Genética médica Medical genetics Efectes secundaris Efectos secundarios Side effects Micro RNAs MicroRNAs Ciències de la Salut 616 |
| topic |
Oncologia Oncología Oncology Radioteràpia Radioterapia Radiotherapy Genètica mèdica Genética médica Medical genetics Efectes secundaris Efectos secundarios Side effects Micro RNAs MicroRNAs Ciències de la Salut 616 |
| description |
Programa de Doctorat en Biomedicina / Tesi realitzada a l'Institut d'Oncologia Vall d’Hebron (VHIO) |
| publishDate |
2024 |
| dc.date.none.fl_str_mv |
2024 2024 2025 |
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info:eu-repo/semantics/doctoralThesis info:eu-repo/semantics/publishedVersion |
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doctoralThesis |
| status_str |
publishedVersion |
| dc.identifier.none.fl_str_mv |
http://hdl.handle.net/10803/691409 |
| url |
http://hdl.handle.net/10803/691409 |
| 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 |
343 p. 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 |
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|
| repository.mail.fl_str_mv |
|
| _version_ |
1869419753624305664 |
| spelling |
Genetic predisposition to radiotherapy-induced toxicityAguado Flor, EsterOncologiaOncologíaOncologyRadioteràpiaRadioterapiaRadiotherapyGenètica mèdicaGenética médicaMedical geneticsEfectes secundarisEfectos secundariosSide effectsMicro RNAsMicroRNAsCiències de la Salut616Programa de Doctorat en Biomedicina / Tesi realitzada a l'Institut d'Oncologia Vall d’Hebron (VHIO)[eng] During radiotherapy (RT) some healthy tissues are irradiated inevitably causing side effects, without being able to predict nowadays which patients will develop this toxicity. To date, the biomarker with the best evidence as a predictive test of late reactions is the radiation-induced lymphocyte apoptosis (RILA) assay. This thesis delves into exploring genetic predispositions to radiation-induced toxicities by analysing gene expression, single nucleotide polymorphisms (SNPs), and microRNA data in patients experiencing toxicity We first aimed to investigate the molecular basis underlying the distinctive RILA levels in patients with toxicity by using gene expression analysis in patients with and without late effects and in whom we had previously identified differences in RILA levels. Peripheral blood mononuclear cells of 10 breast cancer (BC) patients with late severe side effects and 10 patients without symptoms were mock-irradiated or irradiated with 8 Gy. The 48-h response was analysed in parallel by RILA assay and gene expression profiling with Affymetrix microarrays. While the differentially expressed mRNAs did not reach a significant adjusted p-value when comparing patients experiencing clinical toxicity versus those without, the enriched pathways revealed substantial differences between these groups. We found that patients at risk of developing late toxicity have a distinctive pathway signature driven by deregulation of immune and cell cycle pathways related to senescence, which in turn may underlie their low RILA phenotype. Secondly, we investigated the ability of a genetic profile, comprising candidate SNPs located in non-coding RNAs and variants previously linked to toxicity, to predict for RT- induced side effects in BC patients, and to create predictive models integrating the SNPs with relevant clinical variables. The study included 1,979 BC patients followed for two up to eight years after RT as part of a multi-centre study. We split the patient cohort into training and validation datasets according to recruiting centre. In the validation set, SNP- based models showed limited predictive power for both acute and late toxicity (0.49 and 0.54 AUC, respectively). The model using clinical variables alone or the combination of clinical and SNPs had the same performance with an AUC of 0.60 for acute and a c-index of 0.59 for late toxicity. In contrast, accuracy improved in the combination model, reaching 62% for acute and 57% for late toxicity. Our findings did not support a predictive value for the set of assessed non-coding RNA variants and underscore the significance of adding clinical data alongside genetic markers to model for RT toxicity in BC. Lastly, we aimed to identify differentially expressed microRNAs as novel biomarkers for radiosensitivity in whole blood of BC and prostate cancer (PC) patients. Small RNA sequencing was conducted in a discovery cohort, comprising 136 BC and 122 PC patients. Subsequently, a separate cohort was utilized for the validation of the top microRNAs, which included 205 BC patients along with 248 PC patients. In the BC cohort, 90 significantly differentially expressed microRNAs were identified between patients experiencing overall toxicity and those without it. We found pathways related to cellular senescence, transcription and signalling by TGFβ family members upregulated in the toxicity group. In the validation phase, we identified five microRNAs that maintained significant differential expression and fold change direction for BC patients. For the PC cohort, we did not find differentially expressed microRNAs or pathways between cases and controls. However, it is worth noting that we detected nine significant enriched pathways with a non-adjusted p ≤ 0.01 mainly related to cellular senescence and interleukin signalling. Although without adjusted significance, we confirmed in the validation cohort, the under-expression of one microRNA in patients with urinary retention compared to PC patients without toxicity. In summary, our research underscores molecular pathways linked to senescence potentially influencing both the observed late toxicity and RILA phenotype. Our developed predictive models emphasize the significance of integrating relevant clinical variables for toxicity prediction and indicated the limited predictive capability of the studied candidate SNPs. Additionally, we identified a five-microRNA signature that holds promise as a potential biomarker for predicting toxicity outcomes in BC patients.Universitat de BarcelonaGutiérrez Enríquez, SaraGiralt López de Sagredo, JordiSànchez, Àlex (Sànchez Pla)Universitat de Barcelona. Facultat de Biologia202420252024info:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/publishedVersion343 p.application/pdfhttp://hdl.handle.net/10803/691409TDX (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:10803/6914092026-06-14T12:46:07Z |
| score |
15,198674 |