Unravelling genetic predisposition to familial breast and ovarian cancer: new susceptibility genes and variant interpretation by in silico approaches

Autor/a

Moles Fernández, Alejandro

Director/a

Gutiérrez Enríquez, Sara

Díez Gibert, Orland

Tutor/a

Sànchez, Àlex (Sánchez Pla)

Fecha de defensa

2022-01-31

Páginas

275 p.



Departamento/Instituto

Universitat de Barcelona. Facultat de Biologia

Resumen

Patients with hereditary breast and ovarian cancer (HBOC) in whom a causative pathogenic variant is not identified after genetic analysis may not benefit from prevention, early detection, or precision treatment measures. This negative or inconclusive results are due, among other causes, to the detection of variants of uncertain significance (VUS).The main objective of this thesis is to increase the capacity of genetic diagnosis of patients with HBOC, by focusing on i) the optimisation in the interpretation of exonic and intronic variants that might affect RNA quality or quantity but remain as variants of uncertain significance (VUS) and ii) the identification of new susceptibility genes for HBOC. The article included in this thesis, Moles-Fernández et al., 2018 (DOI: 10.3389/fgene.2018.00366) explains an optimization in the identification of potentially spliceogenic variants located near to splicing sites, and provides recommendations to use for analysing donor and acceptor sites. Moreover, the creation or activation of cryptic sites along deep intronic regions could alter splicing causing the inclusion of intronic sequences in RNA. In the article, Moles-Fernández et al., 2021 (DOI: 10.3390/cancers13133341), a framework for the identification of deep intronic spliceogenic is provided, after the performance analysis of SpliceAI in silico tool in a dataset of spliceogenic and non-spliceogenic deep intronic variants. In addition, the importance of the splicing regulatory elements balance in the pseudoexon creation is described. The American College of Medical Genetics (ACMG) variant interpretation guidelines provide general recommendations to classify variants. In the included article Feliubadalò et al., 2021 (DOI: 10.1093/clinchem/hvaa250), ACMG guidelines were adapted to ATM gene. We focused on in silico splicing evidence (PP3/BP4). After reclassification of variants following the adapted guidelines, a reduction of VUS was obtained. On the other hand, in patients without pathogenic variants identified in HBOC related genes, the phenotype could be due to deleterious variants in genes still not known associated with the disease. For this reason, in Moles-Fernández et al., (article in preparation), the aim was to identify candidate genes through exomes and extended panel analysis and validate their risk association by performing a case-control study. The significant identification of loss-of-function variants in ALKBH3, BLM, CAMKK1, FANCD2, FANCM, NEIL3, PER1, RBL1, RECQL4, WRN and XRCC4 genes in patients with HBOC suggests that they might be breast/ovarian cancer susceptibility genes.

Palabras clave

Genètica mèdica; Genética médica; Medical genetics; Oncologia; Oncología; Oncology; Simulació per ordinador; Simulación por ordenador; Computer simulation

Materias

575 - Genética general. Citogenética general. Inmunogenética. Evolución. Filogenia

Área de conocimiento

Ciències Experimentals i Matemàtiques

Nota

Programa de Doctorat en Biomedicina / Tesi realitzada a l'Institut d'Oncologia Vall d’Hebron (VHIO)

Documentos

AMF_PhD_THESIS.pdf

44.26Mb

 

Derechos

L'accés als continguts d'aquesta tesi queda condicionat a l'acceptació de les condicions d'ús establertes per la següent llicència Creative Commons: http://creativecommons.org/licenses/by/4.0/
L'accés als continguts d'aquesta tesi queda condicionat a l'acceptació de les condicions d'ús establertes per la següent llicència Creative Commons: http://creativecommons.org/licenses/by/4.0/

Este ítem aparece en la(s) siguiente(s) colección(ones)