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Universidad Autónoma De Madrid Search for New Susceptibility Genes in Hereditary BRCAX Families with an Apparent Recessive Patt

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Universidad Autónoma De Madrid Search for New Susceptibility Genes in Hereditary BRCAX Families with an Apparent Recessive Patt Universidad Autónoma de Madrid Departamento de Bioquímica Doctoral Thesis Search for new susceptibility genes in hereditary BRCAX families with an apparent recessive pattern of inheritance using Whole Exome Sequencing Alejandra Tavera Tapia Madrid, 2017 1 Universidad Autónoma de Madrid Facultad de Medicina Departamento de bioquímica Search for new susceptibility genes in hereditary BRCAX families with an apparent recessive pattern of inheritance using Whole Exome Sequencing Doctoral Thesis MSc in Cell Biology Alejandra Tavera Tapia Thesis Directors Dr. Ana Osorio Cabrero Dr. Javier Benítez Ortiz Human Genetics Group Human Cancer Genetics Programme Spanish National Cancer Research Centre 3 This thesis, submitted for the degree of Doctor of Philosophy at the Autonomous University of Madrid, has been elaborated in the Human Cancer Genetics laboratory at the Spanish National Cancer Research Center (CNIO), under the supervision of Dr. Ana Osorio Cabrero and Dr. Javier Benítez Ortíz. This research was supported by the following grants and fellowships: La Caixa/CNIO International PhD Fellowship, 2013-2017: Alejandra Tavera Tapia Boehringer Ingelheim Fonds Travel Fellowship, 2016: Alejandra Tavera Tapia The Spanish Ministry of Economy and Competitiveness (MINECO) SAF2014-57680- R. The Spanish Health Ministry PI12/00070, FEDER funds and H2020 (BRIDGES project, number 634935), and FIS 15/00059 Project “300 exomes to elucidate rare diseases” by National Center for Genomic Analysis (CNAG) CIBERER 9 Summary 11 Only two genes involved in high-risk breast/ovarian cancer hereditary syndrome (HBOC) have been identified, BRCA1 and BRCA2, that do not explain more than 20% of all the HBOC cases. In the last years, Whole Exome Sequencing (WES) has been used to find new high susceptibility genes. Although initial attempts were not as conclusive as expected; recently, novel susceptibility genes for HBOC have been reported using WES. Thus, the main objective of this study is the quest for new high susceptibility genes in BRCAX hereditary breast cancer families with an apparent recessive pattern of inheritance, which has remained largely unexplored. After reviewing about 2000 stories of familial breast cancer, we selected four families showing an apparent pattern of monogenic recessive inheritance with the following characteristics: presence of two or more affected siblings with breast cancer at young age, absence of familial antecedents of the disease, availability of the samples and no mutations in BRCA1 and BRCA2 genes. In our first approach, studying the recessive model of inheritance, we found 14 candidate variants in two families where the exomes from the parents and the affected siblings was accessible (family 1 and 2). After that, regardless of the inheritance model, we explored the genes related with DNA repairing and maintenance systems, where we found a novel mutation in ATM (c.5441delT; p.Leu1814Trpfs*14), an already recognized gene for hereditary breast cancer, as a causal variant in a BRCAX family. We found other family with variants affecting RECQL5 gene (1709C>T, p. T570I and c.2874C>G, p. S958R), an excellent candidate to be associated with the disease. As we had found at least one family where the dominant model explained the cause of the disease, we completed the panorama by studying the rest of the genes under this model in the three families. We ended up with a total of 43 candidate variants from which we finally selected 25 as putative susceptibility alleles for hereditary breast cancer after performing a case-control association study in 1,500 cases of BRCAX families and 500 controls in Spanish population. We performed full coding sequencing and exon-boundaries analysis of RECQL5 and ATM, in order to establish the frequency and spectrum of mutations of both genes in Spanish population. Regarding RECQL5, Truseq platform from Illumina was used in a cohort of 700 BRCAX BC-only cases and 754 controls. From this study, we propose RECQL5 as a novel BC susceptibility gene, by the identification of clearly deleterious mutations in the BRCAX cohort studied. Other potentially deleterious mutations were identified and in silico studies predict them to affect preferentially helicase domain of this enzyme. Concerning ATM, Next Generation Sequencing panels were used for ATM mutational screening in a cohort of 392 HBOC Spanish BRCAX families and 350 controls. 1.78% prevalence of mutations in the ATM gene was associated to HBOC and 1.94% in breast cancer-only BRCAX families in Spanish population. In the fourth family, which is a family with various cases of male breast cancer (MBC), we explored the recessive model and the X-linked inheritance model. Seven candidate variants were identified as putative susceptibility alleles for MBC, which were studied in an initial cohort of 50 Spanish hereditary MBC cases and in an enlarged cohort of 1200 MBC and 500 controls from UK. In the Spanish cohort, we found another MBC case that was homozygous for c.1208G>A p.R403Q affecting TXNDC5 gene which is involved in the Androgen Receptor pathway and therefore we propose as a novel putative susceptibility allele for MBC, that requires further study. In conclusion, these set of studies using WES for exploring HBOC missing hereditability has guided to the exploration of different models of inheritance and has been useful to find new BC susceptibility candidate genes, as well as variants not previously reported in well-established BC susceptibility genes, which contributes to the understating of the still uncovered BRCAX landscape. 13 Resumen 15 Sólo dos genes que confieren alta susceptibilidad al síndrome de cáncer de mama y ovario hereditario (CMOH) han sido identificados, BRCA1 y BRCA2, que no explican más del 20% de todos los casos de CMOH. La secuenciación completa de exoma ha sido empleada para encontrar nuevos genes que confieran alta susceptibilidad a HBOC. Así, el objetivo principal de este estudio es la búsqueda de nuevos genes de alta susceptibilidad en familias de cáncer de mama hereditario BRCAX con un patrón aparente de herencia recesiva mediante el uso de secuenciación de exoma completo. Después de revisar 2000 historias clínicas de cáncer de mama familiar, hemos seleccionado cuatro familias que muestran un patrón aparente de herencia monogénica recesiva: presencia de dos o más hermanas afectadas con cáncer de mama en edad joven, ausencia de antecedentes familiares de la enfermedad y ninguna mutación en los genes BRCA1 y BRCA2 (BRCAX). Estudiando el modelo de herencia recesivo, encontramos 14 variantes candidatas en dos familias donde los exomas de los padres y las hijas afectas con cáncer de mama estaban disponibles (familia 1 y 2). Después, independientemente del modelo de herencia, exploramos genes relacionados con sistemas de reparación y mantenimiento del DNA, donde encontramos una mutación no reportada previamente en ATM (c.5441delT; p.Leu1814Trpfs*14), un gen previamente reconocido como un gen de susceptibilidad a cáncer de mama, como la variante causal en una familia BRCAX. También, encontramos otra familia con dos variantes en el gen RECQL5 (1709C>T, p. T570I y c.2874C>G, p.S958R), que consideramos un excelente candidato posiblemente relacionado con la enfermedad. Dado que encontramos al menos una familia donde el modelo dominante explicaba la causa de la enfermedad, completamos el panorama estudiando el resto de genes bajo este modelo de herencia en las tres familias. De las 43 variantes candidatas iniciales, identificamos 25 como alelos putativos de susceptibilidad a cáncer de mama hereditario, seleccionadas a través de un estudio de asociación de casos y controles efectuado en 1500 casos de familias BRCAX y 500 controles de población española. Realizamos la secuenciación completa de regiones codificantes en RECQL5 y ATM, a fin de establecer la frecuencia y espectro de las mutaciones de ambos genes en población española. En cuanto a RECQL5, el gen fue analizado utilizando la plataforma Truseq de Illumina en una cohorte de 700 casos de mama de familias BRCAX y 754 controles. De este estudio, proponemos RECQL5 como un nuevo gen que confiere susceptibilidad a cáncer de mama por la identificación de mutaciones claramente deletéreas en la cohorte de casos BRCAX. Otras mutaciones potencialmente deletéreas fueron identificadas y los estudios in silico predicen que afectan preferencialmente al dominio helicasa de esta enzima. Con respecto a ATM, se usó un panel de secuenciación de nueva generación para su análisis mutacional en una cohorte de 392 CMOH de familias BRCAX y 350 controles. Se encontró una prevalencia de 1.78% de mutaciones el gen ATM asociada con CMOH y 1.94% asociada a cáncer de mama en familias BRCAX en población española. En la cuarta familia, caracterizada por la presencia de varios casos de cáncer de mama en varón (CMV), exploramos el modelo recesivo y de herencia ligado al X. Siete variantes candidatas fueron identificadas como alelos putativos de susceptibilidad a CMV, las cuales fueron estudiados en una cohorte inicial de 50 casos de CMV hereditarios de población española y en una cohorte de 1200 CMV y 500 controles de población inglesa. En población española, encontramos otro caso de CMV que era homocigoto para c.1208G>A p.R403Q, afectando el gen TXNDC5, relacionado con la ruta del receptor de andrógenos, el cual proponemos como un gen candidato de susceptibilidad al CMV hereditario que requiere más estudios moleculares. En conclusión, este conjunto de estudios usando la secuenciación de exoma completo ha sido útil para encontrar nuevos genes candidatos que confieren susceptibilidad a cáncer de mama, así como variantes no reportadas previamente en genes de susceptibilidad a cáncer de mama ya establecidos como tales, lo cual contribuye a entender una parte del panorama aún irresuelto de los casos BRCAX. 17 Table of contents 19 Table of contents 1. Abbreviations 23 2. Introduction 27 2.1. Breast cancer 2.1.1 Mammary gland anatomy and breast cancer 29 2.1.2 Epidemiology 34 2.1.3 Risk factors 34 2.2.
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