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Tesis por compendio de publicaciones, [ES] Profundizar en los determinantes biológicos causantes de la iniciación, progresión y evolución clonal de la LLC con del(11q), así como explorar nuevas vulnerabilidades terapéuticas en este subgrupo de pacientes, mediante la combinación de técnicas de secuenciación masiva, modelos in vitro isogénicos editados mediante CRISPR/Cas9, modelos de xenotrasplante murino in vivo y cultivos ex vivo de células primarias de LLC. Para ello Analizar la presencia de mutaciones génicas y alteraciones cromosómicas en progenitores hematopoyéticos CD34+de pacientes de LLC para determinar el estadio de maduración. Determinar el perfil mutacional de los enfermos de LLC con del(11q) para identificar patrones preferentes de concurrencia o mutual exclusividad con relevancia clínica. Generar modelos isogénicos de LLC que reproduzcan la biología de la del(11q) y/o mutaciones de pérdida de función asociadas en los genes ATM, TP53 o BIRC3 mediante el sistema de edición genómica CRISPR/Cas9. Evaluar el impacto funcional de la pérdida monoalélica y bialélica de ATM en la LLC con del(11q) a nivel de señalización en respuesta a daño en el ADN e identificar potenciales vulnerabilidades terapéuticas de este subgrupo de pacientes basadas en letalidad sintética. Caracterizar el impacto biológico de la concurrencia de alteraciones monoalélicas y bialélicas en los genes ATM y TP53 en la LLC con del(11q) a nivel in vitro e in vivo. Dilucidar el efecto biológico de la pérdida de BIRC3 mediada por del(11q) y/o mutaciones de pérdida de función de BIRC3 en la señalización de NF-κB y en la desregulación de la apoptosis.

[ES] En 2017 la Organización Mundial de la Salud lanzó un informe del Sistema Mundial de Vigilancia de Resistencia a los Antimicrobianos GLobal Antimicrobial Resistance Surveillance System (GLASS report) donde se reportaron altos niveles de resistencia antimicrobiana en los diferentes países del mundo, y las acciones a implementar para evitar el incremento de este problema de salud pública (OMS, 2017).

[ES] Una cuestión clínica importante en el manejo de la enfermedad tromboembólica venosa (ETEV) es cómo seleccionar a los candidatos a anticoagulación prolongada. Según las guías actuales, para mantener el tratamiento anticoagulante debe evaluarse, en primer lugar, el tipo de evento tromboembólico: “provocado” (con factores de riesgo transitorios o persistentes) o “no provocado” (sin factores de riesgo identificados), así como determinar periódicamente los riesgos de hemorragia y de recurrencia. La categorización de los factores de riesgo para ETEV, es importante para valorar riesgo de recurrencia, y consecuentemente para tomar decisiones sobre la duración de la anticoagulación. Nuestro interés se centra en determinar las características clínicas y biológicas del tromboembolismo pulmonar (TEP) no provocado y también en la identificación de nuevos factores de riesgo con la relevancia que puedan tener las mutaciones relacionadas con la hematopoyesis clonal de significado indeterminado (CHIP).

Background: There is an urgent need to identify biomarkers to guide personalized therapy in castration-resistant prostate cancer (CRPC). We aimed to clinically qualify androgen receptor (AR) gene status measurement in plasma DNA using multiplex droplet digital PCR (ddPCR) in pre- and post-chemotherapy CRPC. Methods: We optimized ddPCR assays for AR copy number and mutations and retrospectively analyzed plasma DNA from patients recruited to one of the three biomarker protocols with prospectively collected clinical data. We evaluated associations between plasma AR and overall survival (OS) and progression-free survival (PFS) in 73 chemotherapy-naive and 98 postdocetaxel CRPC patients treated with enzalutamide or abiraterone (Primary cohort) and 94 chemotherapy-naive patients treated with enzalutamide (Secondary cohort; PREMIERE trial). Results: In the primary cohort, AR gain was observed in 10 (14%) chemotherapy-naive and 33 (34%) post-docetaxel patients and associated with worse OS [hazard ratio (HR), 3.98; 95% CI 1.74-9.10; P= 50% [odds ratio (OR), 4.7; 95% CI 1.17-19.17; P = 0.035 and OR, 5.0; 95% CI 1.70-14.91; P = 0.003, respectively]. ARmutations [2105T>A (p.L702H) and 2632A>G (p.T878A)] were observed in eight (11%) post-docetaxel but no chemotherapy-naive abiraterone-treated patients and were also associated with worse OS (HR 3.26; 95% CI 1.47-not reached; P = 0.004). There was no interaction between AR and docetaxel status (P = 0.83 for OS, P = 0.99 for PFS). In the PREMIERE trial, 11 patients (12%) with AR gain had worse PSA-PFS (sPFS) (HR 4.33; 95% CI 1.94-9.68; P, This work was funded by Prostate Cancer UK (PG12-49) and Cancer Research UK (A13239) and was supported by the NIHR Royal Marsden and the Institute of Cancer Research (ICR) Biomedical Research Centre. VC was funded by a European Society of Medical Oncology Translational Clinical Research Fellowship, AJ by an Irish Health Research Board Clinical Research Fellowship and a Medical Research Council Clinical Research Fellowship, DGT by a European Union Marie Curie Intra-European Postdoctoral Fellowship, EG by Instituto de Salud Carlos III and the Spanish Society of Medical Oncology (SEOM)/Chris Foundation (no grant numbers apply) and GA by a Cancer Research UK Advanced Clinician Scientist Fellowship. The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The PREMIERE trial was sponsored by Spanish Genito-Urinary oncology Group that received a grant from Astellas to support the conduct of the trial.

Introduction: CHARGE syndrome is a multisystem disorder that, in addition to Kallmann syndrome/isolated hypogonadotrophic hypogonadism, has been associated with anterior pituitary hypoplasia (APH). However, structural abnormalities such as an ectopic posterior pituitary (EPP) have not yet been described in such patients. Objective: The aims of the study were: 1) to describe the association between CHARGE syndrome and a structurally abnormal pituitary gland; and 2) to investigate whether CHD7 variants, which are identified in 65% of CHARGE patients, are common in septo-optic dysplasia/hypopituitarism. Methods: We describe 2 patients with features of CHARGE and EPP. CHD7 was sequenced in these and other patients with septo-optic dysplasia/hypopituitarism. Results: EPP, APH, and GH, TSH, and probable LH/FSH deficiency were present in 1 patient, and EPP and APH with GH, TSH, LH/FSH, and ACTH deficiency were present in another patient, both of whom had features of CHARGE syndrome. Both had variations in CHD7 that were novel and undetected in control cohorts or in the international database of CHARGE patients, but were also present in their unaffected mothers. No CHD7 variants were detected in the patients with septo-optic dysplasia/hypopituitarism without additional CHARGE features. Conclusion: We report a novel association between CHARGE syndrome and structural abnormalities of the pituitary gland in 2 patients with variations in CHD7 that are of unknown significance. However, CHD7 mutations are an uncommon cause of septo-optic dysplasia or hypopituitarism. Our data suggest the need for evaluation of pituitary function/anatomy in patients with CHARGE syndrome. (J Clin Endocrinol Metab 98: E737-E743, 2013), This work was supported by a project grant from Birth Defects Foundation-Newlife (08-09/29 to M.J.M. and M. T. D.); in part by a grant from the British Society for Pediatric Endocrinology and Diabetes (to M. T. D.); and the Wellcome Trust (Grants 084361 and 086545; to M. T. D. and L. C. G.). M. T. D. is also funded by Great Ormond Street Hospital Children's Charity.

[Objective] To study the molecular genetic and clinical features of cerebral cavernous malformations (CCM) in a cohort of Spanish patients., [Methods] We analyzed the CCM1, CCM2, and CCM3 genes by MLPA and direct sequencing of exons and intronic boundaries in 94 familial forms and 41 sporadic cases of CCM patients of Spanish extraction. When available, RNA studies were performed seeking for alternative or cryptic splicing., [Results] A total of 26 pathogenic mutations, 22 of which predict truncated proteins, were identified in 29 familial forms and in three sporadic cases. The repertoire includes six novel non-sense and frameshift mutations in CCM1 and CCM3. We also found four missense mutations, one of them located at the third NPXY motif of CCM1 and another one that leads to cryptic splicing of CCM1 exon 6. We found four genomic deletions with the loss of the whole CCM2 gene in one patient and a partial loss of CCM1and CCM2 genes in three other patients. Four families had mutations in CCM3. The results include a high frequency of intronic variants, although most of them localize out of consensus splicing sequences. The main symptoms associated to clinical debut consisted of cerebral haemorrhage, migraines and epileptic seizures. The rare co-occurrence of CCM with Noonan and Chiari syndromes and delayed menarche is reported., [Conclusions] Analysis of CCM genes by sequencing and MLPA has detected mutations in almost 35% of a Spanish cohort (36% of familial cases and 10% of sporadic patients). The results include 13 new mutations of CCM genes and the main clinical symptoms that deserves consideration in molecular diagnosis and genetic counselling of cerebral cavernous malformations., This work has been supported by grants CP10/00526 (Instituto de Salud Carlos III, Spain) and P07-CVI-02790 (Junta de Andalucía, Spain). RM received a fellowship of José Luis Castaño Foundation.

Background: Hereditary Spastic Paraplegias (HSP) are characterized by progressive spasticity and weakness of the lower limbs. At least 45 loci have been identified in families with autosomal dominant (AD), autosomal recessive (AR), or X-linked hereditary patterns. Mutations in the SPAST (SPG4) and ATL1 (SPG3A) genes would account for about 50% of the ADHSP cases. Methods: We defined the SPAST and ATL1 mutational spectrum in a total of 370 unrelated HSP index cases from Spain (83% with a pure phenotype). Results: We found 50 SPAST mutations (including two large deletions) in 54 patients and 7 ATL1 mutations in 11 patients. A total of 33 of the SPAST and 3 of the ATL1 were new mutations. A total of 141 (31%) were familial cases, and we found a higher frequency of mutation carriers among these compared to apparently sporadic cases (38% vs. 5%). Five of the SPAST mutations were predicted to affect the pre-mRNA splicing, and in 4 of them we demonstrated this effect at the cDNA level. In addition to large deletions, splicing, frameshifting, and missense mutations, we also found a nucleotide change in the stop codon that would result in a larger ORF. Conclusions: In a large cohort of Spanish patients with spastic paraplegia, SPAST and ATL1 mutations were found in 15% of the cases. These mutations were more frequent in familial cases (compared to sporadic), and were associated with heterogeneous clinical manifestations., This work was supported by grants from Spanish Fondo de Investigaciones Sanitarias PI08/0915 (European FEDER founds) to V. A. E. S-F. was a fellowship from FICYT-Principado de Asturias. The authors thank the patients and family members for their participation in this study. Authors wish to thank Fundacion Parkinson Asturias and Obra Social CAJASTUR for their support.