Tumour mutations in long noncoding RNAs enhance cell fitness

Long noncoding RNAs (lncRNAs) are linked to cancer via pathogenic changes in their expression levels. Yet, it remains unclear whether lncRNAs can also impact tumour cell fitness via function-altering somatic “driver” mutations. To search for such driver-lncRNAs, we here perform a genome-wide analysis of fitness-altering single nucleotide variants (SNVs) across a cohort of 2583 primary and 3527 metastatic tumours. The resulting 54 mutated and positivelyselected lncRNAs are significantly enriched for previously-reported cancer genes and a range of clinical and genomic features. A number of these lncRNAs promote tumour cell proliferation when overexpressed in in vitro models. Our results also highlight a dense SNV hotspot in the widely-studied NEAT1 oncogene. To directly evaluate the functional significance of NEAT1 SNVs, we use in cellulo mutagenesis to introduce tumour-like mutations in the gene and observe a significant and reproducible increase in cell fitness, both in vitro and in a mouse model. Mechanistic studies reveal that SNVs remodel the NEAT1 ribonucleoprotein and boost subnuclear paraspeckles. In summary, this work demonstrates the utility of driver analysis for mapping cancer-promoting lncRNAs, and provides experimental evidence that somatic mutations can act through lncRNAs to enhance pathological cancer cell fitness.Swiss National Science Foundation through the National Centre of Competence in Research (NCCR) "RNA amp; Disease" 51NF40-182880The elements of long noncoding RNA function 31003A_182337Sinergia project "Regenerative strategies for heart disease via targeting the long noncoding transcriptome" 173738Medical Faculty of the University and University Hospital of BernHelmut Horten Stiftung, Swiss Cancer Research Foundation 4534-08-2018Science Foundation Ireland 18/FRL/6194 18/CRT/621

Deportes en los Juegos Olímpicos: Su reflejo en los medios de comunicación y buscadores

Los Juegos Olímpicos modernos están cambiando, y lo hacen con los tiempos y nuevas generaciones. Esto ha supuesto también un importante papel de los medios de comunicación, cuya repercusión afecta de manera activa a incentivar las opciones de que una disciplina se incluya en el programa olímpico por parte del Comité Olímpico Internacional. En este trabajo resaltaremos la importancia que juegan los medios de comunicación una vez las distintas disciplinas y deportes son aceptadas para ser olímpicas en las próximas citas de Tokio 2020 y París 2024. Lo haremos con una perspectiva popular, ya que elegiremos deportes que tienen un pasado en las calles, barrios o playas de diversas partes del mundo. Para ello analizando las noticias editadas en los medios de comunicación y las búsquedas en los distintos motores de internet llegaremos a las conclusiones sobre si afectan y de qué manera a la popularidad de los mismos. Este trabajo pone de manifiesto la relevancia de los medios de comunicación y su interpolación a los lectores y consumidores de prensa no solo deportiva sino también generalista y el impacto que esta tiene en el interés de los mismos a la hora de buscar e indagar de manera proactiva en internet.The Olympic Games are changing, and it comes with the times and new generations. Mass Medias have had an important role in those changes and how they could affect to th e sports, as they could even be key for the decision taken by the CIO to include them into the Olympic program for the next Olympic Games. The following work tries to highlight the importance of the media once the different disciplines and sports were ac cepted to be part of the Olympic program for the nexts Olympic Games in Tokyo 2021 and Paris 2024. Also we’ll use a popular perspective, using sports that were born in the streets, beaches or neighborhoods from cities around the world. To analyze this, we took some of the most important newspapers in Spain and checked the number of news published since the CIO announced they will be an Olympic Sport and also will check the different searching volumes for those keywords to see how this affects the searches o n Google. Importance of the mass media and its interpolation to readers and consumers, no only on specialized press but also the generic one. We show the impact of them on the search volume on the Internet.Universidad de Sevilla. Grado en Periodism

Supplementing nursery pig feed with seaweed extracts increases final body weight of pigs

Probiotics have been used as an alternative method to antibiotic treatment. In this study, we evaluated the effect of seaweed extracts, commercially named OceanFeed Swine® (OFS), on body weight, average daily weight gain (ADG) and feed efficiency (FE) in nursery and fattening pigs of terminal lines. The study was conducted with 1809 piglets from weaning age until the end of the fattening phase on a commercial farm, divided into two groups (control and OFS; 905 and 904 pigs, respectively). Three replicates were made during the 6 weeks of production. Food was elaborated in the same productive unit and was given to the animals in the form of flour. OceanFeed Swine® (5 g/kg of diet) was added to the diet of the OFS groups during the nursery period, from 21 to 55 days of age. The faecal microbial population was evaluated at 35 and 60 days of life. In this paper, we observed a positive effect of administering OceanFeed Swine® on the production parameters analysed in the fattening phase, showing an improvement of 26 g in ADG and FE of 0.07. It can be concluded that the use of OceanFeed Swine® in the diets of the piglets, aged between 21 to 55 days old, improves FE (Control 2.36, OFS 2.29) and ADG (control 0.798 kg, OFS 0.824 kg). Moreover, its use exhibited an increase in the slaughter weight, a reduction of E coli CFU, and an increase in Lactobacillus sp. in fattening animals. All these improvements have a major positive economic impact per pig at time of slaughter

The value of desmosomal plaque-related markers to distinguish squamous cell carcinoma and adenocarcinoma of the lung

An antibody panel is needed to definitively differentiate between adenocarcinoma (AC) and squamous cell carcinoma (SCC) in order to meet more stringent requirements for the histologic classification of lung cancers. Staining of desmosomal plaque-related proteins may be useful in the diagnosis of lung SCC. The specificity for SCC of membrane staining for PKP1, KRT15, and DSG3 was 97.4%, 94.6%, and 100%, respectively, and it was 100% when the markers were used together and in combination with the conventional markers (AUCs of 0.7619 for Panel 1 SCC, 0.7375 for Panel 2 SCC, 0.8552 for Panel 1 AC, and 0.8088 for Panel 2 AC). In a stepwise multivariate logistic regression model, the combination of CK5/6, p63, and PKP1 in membrane was the optimal panel to differentiate between SCC and AC, with a percentage correct classification of 96.2% overall (94.6% of ACs and 97.6% of SCCs). PKP1 and DSG3 are related to the prognosis. PKP1, KRT15, and DSG3 are highly specific for SCC, but they were more useful to differentiate between SCC and AC when used together and in combination with conventional markers. PKP1 and DSG3 expressions may have prognostic value.MEFV was supported by PAIDI programme, Group BIO309, Junta de Andalucía

Multi‑omic alterations of the SWI/SNF complex define a clinical subgroup in lung adenocarcinoma

PPM's lab is funded by the Ministry of Economy of Spain (SAF2015-67919-R), Junta de Andalucia (P20-00688, PI-0135-2020, PIGE-0213-2020, PIGE-04402019, PI-0245-2017), University of Granada (B-CTS-480-UGR20), International Association for the Study of Lung Cancer (IASLC), and Spanish Association for Cancer Research (LAB-AECC-2018). PP is supported by a PhD "La Caixa Foundation"LCF/BQ/DE15/10360019 Fellowship. AA is supported by an FPU17/00067 fellowship. IFC was supported by a PhD FPI-fellowship (BES-2013-064596). DJG was supported by a "Fundacion Benefica Anticancer Santa Candida y San Francisco Javier"predoctoral fellowship. MSBC and CC's work is supported by the project DPI2017-84439-R Ministry of Economy of Spain and FEDER and by the fellowship "Beca de Iniciacion a la Investigacion del Plan Propio de Investigacion 2019" by University of Granada. MSBC is supported by an FPU19/00576 predoctoral fellowship. CNIO Proteomics Unit is a member of Proteored PRB3 and is supported by grant PT17/0019, of the PE I + D + i 2013-2016, funded by ISCIII and ERDF.SWI/SNF complexes are major targets of mutations in cancer. Here, we combined multiple “-omics” methods to assess SWI/SNF composition and aberrations in LUAD. Mutations in lung SWI/SNF subunits were highly recurrent in our LUAD cohort (41.4%), and over 70% of the mutations were predicted to have functional impact. Furthermore, SWI/ SNF expression in LUAD suffered an overall repression that could not be explained exclusively by genetic alterations. Finally, SWI/SNF mutations were associated with poorer overall survival in TCGA-LUAD. We propose SWI/SNF-mutant LUAD as a separate clinical subgroup with practical implications.Spanish Government SAF2015-67919-R DPI2017-84439-RJunta de Andalucia P20-00688 PI-0135-2020 PIGE-0213-2020 PIGE-0440-2019 PI-0245-2017University of Granada B-CTS-480-UGR20International Association for the Study of Lung Cancer (IASLC)Spanish Association for Cancer Research LAB-AECC-2018La Caixa Foundation LCF/BQ/DE15/10360019PhD FPI-fellowship BES-2013-064596"Fundacion Benefica Anticancer Santa Candida y San Francisco Javier" predoctoral fellowshipEuropean Commissionfellowship "Beca de Iniciacion a la Investigacion del Plan Propio de Investigacion 2019" by University of Granada Instituto de Salud Carlos III PT17/0019European Commission PT17/0019 FPU17/00067 FPU19/0057

ROS-MATLAB HMI for industrial robot teleoperation

[Resumen] ROS (Robot Operating System) es un framework para el desarrollo de sistemas robóticos de código abierto ampliamente utilizado en la industria y la investigación. Los sistemas robóticos asistidos requieren una comunicación fluida y fiable entre ROS y el controlador externo, a fin de lograr un control y supervisión eficaz del mismo. En este artículo, se presenta el procedimiento necesario para establecer la comunicación a través de una red local entre un robot móvil que implementa ROS y un dispositivo remoto desde el que enviar y recibir información del robot. Además, se propone un ejemplo de HMI (Interfaz Hombre-Máquina) desarrollado en MATLAB, y que puede ser instalada en equipos Windows, Linux o MacOSX, para la teleoperación de un robot en un entorno industrial. La comunicación bidireccional en tiempo real, las capacidades de procesamiento de datos y su versatilidad la convierten en una herramienta completa para la gestión de datos robóticos en entornos industriales.[Abstract] ROS (Robot Operating System) is an open-source robotics development framework widely used in industry and research. Human assisted robotic systems require of robust and constant communication between ROS and the remote controller in order to achieve effective control and monitoring of the system. In this paper, we propose a methodology to connect a mobile ROS with a remote device, using a wireless local network. This device serves as link between the robot and the rest of the system. Additionally, an HMI (Human-Machine Interface) developed using MATLAB is presented. The HMI can be implemented in Windows, Linux or MacOSX computers and provides teleoperation capabilities for a robot in an industrial environment. Real-time bidirectional communication, data processing capabilities and intrinsic versatility make this HMI a robust tool for robotic data management in industrial applications.Ministerio Ciencia e Innovación; PLEC2021-007819Comunidad de Madrid; S2018/NMT-433

Comprehensive Analysis of SWI/SNF Inactivation in Lung Adenocarcinoma Cell Models

Simple Summary: Mammalian SWI/SNF complexes regulate gene expression by reorganizing the way DNA is packaged into chromatin. SWI/SNF subunits are recurrently altered in tumors at multiple levels, including DNA mutations as well as alteration of the levels of RNA and protein. Cancer cell lines are often used to study SWI/SNF function, but their patterns of SWI/SNF alterations can be complex. Here, we present a comprehensive characterization of DNA mutations and RNA and protein expression of SWI/SNF members in 38 lung adenocarcinoma (LUAD) cell lines. We show that over 85% of our cell lines harbored at least one alteration in one SWI/SNF subunit. In addition, over 75% of our cell lines lacked expression of at least one SWI/SNF subunit at the protein level. Our catalog will help researchers choose an appropriate cell line model to study SWI/SNF function in LUAD. Abstract: Mammalian SWI/SNF (SWitch/Sucrose Non-Fermentable) complexes are ATP-dependent chromatin remodelers whose subunits have emerged among the most frequently mutated genes in cancer. Studying SWI/SNF function in cancer cell line models has unveiled vulnerabilities in SWI/SNF-mutant tumors that can lead to the discovery of new therapeutic drugs. However, choosing an appropriate cancer cell line model for SWI/SNF functional studies can be challenging because SWI/SNF subunits are frequently altered in cancer by various mechanisms, including genetic alterations and post-transcriptional mechanisms. In this work, we combined genomic, transcriptomic, and proteomic approaches to study the mutational status and the expression levels of the SWI/SNF subunits in a panel of 38 lung adenocarcinoma (LUAD) cell lines. We found that the SWI/SNF complex was mutated in more than 76% of our LUAD cell lines and there was a high variability in the expression of the di erent SWI/SNF subunits. These results underline the importance of the SWI/SNF complex as a tumor suppressor in LUAD and the di culties in defining altered and unaltered cell models for the SWI/SNF complex. These findings will assist researchers in choosing the most suitable cellular models for their studies of SWI/SNF to bring all of its potential to the development of novel therapeutic applications.Ministry of Economy of Spain SAF2015-67919-RJunta de Andalucía CS2016-3 P12-BIO1655 PIGE-0440-2019 Pl-0245-2017 PI-0135-2020University of Granada PPJIA2019-0 B-CTS-126-UGR18International Association for the Study of Lung Cancer (IASLC)Spanish Association for Cancer Research (LAB-AECC)PhD "La Caixa Foundation" LCF/BQ/DE15/10360019"Fundacion Benefica Anticancer Santa Candida y San Francisco Javier" predoctoral fellowshipEuropean Commission 837897Spanish Ministry of Education, Culture and Sports FPU fellowship FPU17/00067 FPU17/01258 FPU18/03709PhD FPI-fellowship BES-2013-064596Fundación Científica de la Asociación Española Contra el Cáncer GCB14-2170Fundación Ramon ArecesInstituto de Salud Carlos III-Fondo de Investigación Sanitaria-Fondo Europeo de Desarrollo Regional `Una manera de hacer Europa' (FEDER) PI19/0009

Estado del arte de la medición de la productividad y la eficiencia técnica en América Latina: Caso Nicaragua

In this article were presented the results of a literature review from textbooks and scientific papers that address theory of "productivity" and "technical efficiency" as two key economic indicators to determine the economic growth reflected a productive unit, an economic sector or a nation. The study found that countries with a higher contribution of technical progress to the change in productivity in the period of 50 years (1960-2010) were analyzed recorded the Argentina, Brazil, Colombia and Ecuador, with indexes of around 0.3%. Furthermore, it is evident that the 19 countries analyzed in this study showed a decreasing technical efficiency, which means that the contribution of TFP that efficiency was negative in all countries. In the case of Nicaragua it was noted that some authors TFP estimated between 0.016 and 0.018 of growth.Rev. iberoam. bioecon. cambio clim. Vol. 1 num 2, 2015, pág. 76-100  En este artículo se plasman los resultados de una revisión bibliográfica de textos y artículos científicos que abordan la teoría de la “Productividad” y de la “Eficiencia técnica” como dos magnitudes económicas claves para determinar el crecimiento económico de una unidad productiva, un sector económico o de una nación. En el estudio se encontró que los países donde se registró una mayor contribución del progreso técnico a la variación de la productividad en el período de 50 años (de 1960-2010) analizado fueron la Argentina, el Brasil, Colombia y el Ecuador, con índices de alrededor del 0,3%. Además, se evidencia que los 19 países analizados en este trabajo registraron una eficiencia técnica decreciente, que supone que el aporte de dicha eficiencia a la PTF fue negativo en todos los países. En el caso de Nicaragua se notó que la PTF algunos autores la estimaron entre un 0.08 y 0.016 de ritmo de crecimiento interanual.Rev. iberoam. bioecon. cambio clim. Vol. 1 num 2, 2015, pág. 76-10

SMARCA4 deficient tumours are vulnerable to KDM6A/UTX and KDM6B/JMJD3 blockade

The authors thank Isabel Bartolessis (Cancer Genetics Group) at IJC for technical assistance. This work was supported by the Spanish Ministry of Economy and CompetitivityMINECO (grant number SAF-2017-82186R, to M.S.-C., and grant PI19/01320 to A. Villanueva) and from the Fundacion Cientifica of the Asociacion Espanola Contra el Cancer (AECC) (grant number GCB14142170MONT) to M.S.-C. A. Villanueva is also funded by the Department of Health of the Generalitat de Catalunya (2014SGR364). O.A. R. received a Juan de la Cierva postdoctoral contract (grant No. IJCI-2016-28201, until November 2019) and an AECC research contract (INVES19045ROME from December 2019). A. Vilarrubi, P.L. and A.A. are supported by pre-doctoral contracts from the Spanish MINECO (FPI-fellowship: PRE2018-084624, BES-2015-072204 and FPU17/00067). M.S. was supported by a Rio Hortega contract from the Instituto de Salud Carlos III (CM17/00180). L.F. received a European Union Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie Actions grant agreement, number 799850.Despite the genetic inactivation of SMARCA4, a core component of the SWI/SNF-complex commonly found in cancer, there are no therapies that effectively target SMARCA4-deficient tumours. Here, we show that, unlike the cells with activated MYC oncogene, cells with SMARCA4 inactivation are refractory to the histone deacetylase inhibitor, SAHA, leading to the aberrant accumulation of H3K27me3. SMARCA4-mutant cells also show an impaired transactivation and significantly reduced levels of the histone demethylases KDM6A/UTX and KDM6B/JMJD3, and a strong dependency on these histone demethylases, so that its inhibition compromises cell viability. Administering the KDM6 inhibitor GSK-J4 to mice orthotopically implanted with SMARCA4-mutant lung cancer cells or primary small cell carcinoma of the ovary, hypercalcaemic type (SCCOHT), had strong anti-tumour effects. In this work we highlight the vulnerability of KDM6 inhibitors as a characteristic that could be exploited for treating SMARCA4-mutant cancer patients.Spanish Ministry of Economy and Competitivity-MINECO SAF-2017-82186R PI19/01320Fundacion Cientifica of the Asociacion Espanola Contra el Cancer (AECC) GCB14142170MONTDepartment of Health of the Generalitat de Catalunya 2014SGR364Juan de la Cierva postdoctoral contract IJCI-2016-28201AECC research contract INVES19045ROMESpanish MINECO PRE2018-084624 BES-2015-072204 FPU17/00067Instituto de Salud Carlos III European Commission CM17/00180European Union Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie Actions grant agreement 79985

Bioinformatic approaches for the discovery of non-coding alterations in cancer

Introduction. Cancer is one of the main causes of premature death worldwide. Cancers arise when cell genomes accumulate driver mutations, which are mutations that improve cell fitness. Driver mutations are a minority among the thousands of mutations present in a typical cancer genome. Although major efforts have been made to identify driver mutations in various cancers, most of them have focused on the protein coding genome, which only represents ~1.1% of the human genome. Part of the ~98.9% of the human genome that does not code for protein contains functional elements, such as regulatory DNA elements, intronic splice regions, untranslated regions of protein coding genes, and non-coding RNA genes. Among non-coding RNAs, microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) may participate in the regulation of gene expression and their expression is often altered in cancer. However, efforts to identify non-coding driver mutations have been rare, and sample sizes in lung adenocarcinoma (LUAD) have been low. In addition, the largest mutational study in diffuse large B-cell lymphoma (DLBCL) to date omitted mutations in intronic splice regions. Objectives. We aimed to computationally identify and characterize novel driver mutations in non-coding DNA in in-house and external LUAD cohorts, with special focus on miRNA genes, lncRNA genes, and intronic splice regions. In addition, we aimed to identify and characterize previously missed mutations in intronic splice sites in external DLBCL datasets. Methods. We performed targeted sequencing of genomic DNA in an in-house cohort of 70 LUAD primary tumors, 27 matched normal samples, and 37 LUAD cell lines. Our design included all human miRNA genes (n = 1881), as well as exons of cancer-related lncRNA genes (n = 908) and protein coding genes (n = 1307). We developed computational pipelines to identify highconfidence somatic variants by combining multiple variant calling tools, and we also applied them to external whole-genome sequencing data of LUAD samples from The Cancer Genome Atlas (N = 59 tumor-normal pairs). In addition, we applied state-of-the-art driver discovery tools to find putative drivers in coding sequences, lncRNAs, miRNAs, intronic splice regions, proximal promoters, and untranslated regions. We assessed the functional relevance of the identified candidate drivers using external genomic, gene expression, and clinical data as well as functional impact scores. Furthermore, we developed a novel pipeline to annotate variants in a miRNA-centric manner, identifying variants that affect seeds and those that disrupt or create sequence motifs that mediate the processing of miRNA primary transcripts. Finally, in DLBCL, we reanalyzed external datasets (combined N = 1711) to identify previously missed recurrent mutations at intronic splice sites, we analyzed the impact of the splice site mutations on RNA processing, and we functionally characterized the most recurrent splice site mutation, which affected CD79B. Results. We successfully detected high-confidence somatic variants in all analyzed datasets. However, driver discovery tools did not perform adequately in our targeted sequencing cohorts of limited size, as one based on functional impact predictions lacked sensitivity in non-coding regions whereas one based on mutation clustering had a high false positive rate. Still, we identified three candidate driver lncRNAs that accumulated mutations so that at least one mutation had high predicted functional impact: TUSC7, SOX2-OT, and ZEB2-AS1. However, the affected lncRNAs had very low expression in external LUAD datasets. This, together with their mutational patterns and the genomic characteristics of their loci, argued against an RNA sequencedependent effect of their mutations. In miRNAs, a mutation in the seed of miR-133b was predicted to have high functional impact and to prevent it from targeting the oncogene EGFR. In addition, we identified mutations that disrupted or created processing motifs in miRNA primary transcripts, such as mutations that disrupted mismatched GHG motifs in mir-7-1, mir-7-2, and mir-139. In intronic splice regions, we found mutations that altered RNA splicing in LUAD driver genes such as MET and RBM10. In promoters and untranslated regions, we detected no high-confidence drivers. In DLBCL, intronic splice site mutations recurrently affected cancer driver genes and caused major RNA aberrations in cis. The most recurrent RNA alteration was intron 4 retention in CD79B. The alteration was caused by recurrent mutations at the fourth splice donor site of CD79B, and it was associated with an increase in the number of B cell receptors in the cell surface and a subsequent increase in oncogenic signaling. Conclusions. Non-coding variants with high predicted functional impact were rare in our LUAD datasets. In addition, it was unclear whether the candidate driver non-coding RNAs in LUAD had RNA sequence-dependent functions. Experimental work will be necessary to confirm whether the candidate driver non-coding RNAs have biological activity in LUAD and whether their activity is altered by the observed mutations. In DLBCL, intronic splice site mutations are recurrent and they can cause major cancer-promoting aberrations in driver genesIntroducción. El cáncer es una de las principales causas de muerte prematura mundialmente. El cáncer se origina cuando los genomas celulares acumulan mutaciones conductoras, que son mutaciones que confieren ventaja selectiva a la célula. Las mutaciones conductoras son una minoría entre las miles de mutaciones que contiene un genoma tumoral promedio. Aunque se han llevado a cabo grandes esfuerzos para identificar mutaciones conductoras en una gran variedad de cánceres, la mayoría de los esfuerzos se han centrado en el genoma codificante de proteína, que tan solo supone ~1,1% del genoma humano. Parte del ~98,9% del genoma humano no codificante de proteína contiene elementos funcionales, tales como ADN regulador, regiones intrónicas de corte y empalme, regiones no traducidas de genes codificantes de proteína y genes de ARN no codificante. Entre los ARNs no codificantes, los microARNs (miARNs) y los ARNs largos no codificantes (ARNlncs) pueden participar en la regulación de la expresión génica y su expresión está a menudo alterada en cáncer. Sin embargo, los esfuerzos para identificar mutaciones conductoras en secuencias no codificantes han sido escasos, y los tamaños de muestra para adenocarcinoma de pulmón (ADC) han sido bajos. Además, el mayor estudio hasta la fecha en linfoma difuso de células B grandes (LDCBG) omitió las mutaciones en regiones intrónicas de corte y empalme. Objetivos. Nuestro objetivo principal fue analizar y caracterizar computacionalmente nuevas mutaciones conductoras en secuencias no codificantes en cohortes propias y externas de ADC, con especial interés en miARNs, ARNlncs y regiones intrónicas de corte y empalme. Un objetivo adicional fue identificar y caracterizar mutaciones previamente no descritas en sitios intrónicos de corte y empalme en datos externos de LDCBG. Métodos. Realizamos secuenciación de DNA genómico dirigida a todos los genes de miARNs humanos (n = 1881), así como a exones de genes de ARNlncs relacionados con cáncer (n = 908) y de genes codificantes de proteína relacionados con cáncer (n = 1307) en una cohorte propia de 70 tumores primarios de LUAD, 27 muestras normales pareadas y 37 líneas celulares de LUAD. Desarrollamos métodos computacionales para identificar variantes somáticas con alta confianza mediante la combinación de múltiples herramientas. Además, aplicamos dichos métodos para analizar datos de secuenciación de genoma completo de muestras de ADC de The Cancer Genome Atlas (N = 59 parejas tumor-normal). Asimismo, aplicamos herramientas de descubrimiento de mutaciones conductoras en secuencias codificantes, ARNlncs, miARNs, regiones intrónicas de corte y empalme, promotores proximales y regiones no traducidas. Determinamos la relevancia funcional de los elementos candidatos a conductores utilizando datos externos genómicos, transcriptómicos y clínicos. Además, desarrollamos una nueva metodología para anotar variantes de una forma miARN-céntrica, pudiendo identificar variantes que afectan a secuencias semilla y aquellas que crean o destruyen motivos de secuencia que median el procesamiento de los transcritos primarios de miARNs. Finalmente, en LDCBG, reanalizamos conjuntos de datos externos (N combinada = 1711) para identificar mutaciones recurrentes en sitios intrónicos de corte y empalme no detectadas en estudios anteriores. Analizamos el impacto de las mutaciones halladas en el procesamiento del ARN afectado, y caracterizamos funcionalmente la mutación más recurrente, que afectaba a CD79B. Resultados. Detectamos exitosamente variantes somáticas con alta confianza en todos los conjuntos de datos analizados. Sin embargo, las herramientas de descubrimiento de mutaciones conductoras no tuvieron un rendimiento adecuado en nuestras cohortes de secuenciación dirigida de tamaño limitado: una herramienta basada en predicciones de impacto funcional tuvo baja sensibilidad en regiones no codificantes, mientras que otra basada en el agrupamiento de mutaciones tuvo una tasa elevada de falsos positivos. No obstante, identificamos tres ARNlncs candidatos a conductores que acumulaban mutaciones tal que al menos una de ellas tenía un alto impacto funcional predicho: TUSC7, SOX2-OT y ZEB2-AS1. Sin embargo, los ARNlncs afectados tenían una expresión extremadamente baja en datos externos de ADC. Esto, unido a sus patrones mutacionales y a las características genómicas de sus loci, hizo improbable que el efecto de sus mutaciones fuese dependiente de la secuencia de ARN. En miARNs, una mutación en la semilla de miR-133b tenía un alto impacto funcional predicho, impidiendo la unión de miR-133b al oncogén EGFR. Asimismo, identificamos mutaciones que destruían o creaban motivos de procesamiento en los transcritos primarios de miARNs, destacando las mutaciones que afectaban a motivos GHG desapareados en mir-7-1, mir-7-2 y mir-139. En regiones intrónicas de corte y empalme, hallamos mutaciones que alteraban el corte y empalme de genes conductores de ADC como MET y RBM10. En promotores y en regiones no traducidas, no encontramos ninguna mutación conductora con alto nivel de confianza. En LDCBG, las mutaciones en sitios intrónicos de corte y empalme afectaban recurrentemente a genes conductores de la enfermedad y causaban grandes aberraciones a nivel de ARN en cis. La aberración más recurrente a nivel de ARN fue la retención del intrón 4 de CD79B. La alteración estaba causada por mutaciones recurrentes en el cuarto sitio intrónico donador de corte y empalme de CD79B, y estaba asociada a un incremento en el número de receptores de células B en la superficie celular y un consiguiente aumento en la señalización oncogénica. Conclusiones. Las variantes en ARNs no codificantes con impacto funcional predicho elevado fueron infrecuentes en nuestros conjuntos de datos. Asimismo, no se pudo determinar de manera concluyente que los ARNs no codificantes candidatos a conductores de ADC tuviesen funciones dependientes de la secuencia de ARN. Se requerirá trabajo experimental para confirmar si los ARNs no codificantes candidatos a conductores tienen actividad biológica en ADC y si las mutaciones detectadas en los mismos alteran dicha actividad. En LDCBG, las mutaciones en sitios intrónicos de corte y empalme son recurrentes y pueden causar grandes aberraciones en los principales genes conductores de la enfermedad.Tesis Univ. Granada