Applications of the ACGT Master Ontology on Cancer

In this paper we present applications of the ACGT Master Ontology (MO) which is a new terminology resource for a transnational network providing data exchange in oncology, emphasizing the integration of both clinical and molecular data. The development of a new ontology was necessary due to problems with existing biomedical ontologies in oncology. The ACGT MO is a test case for the application of best practices in ontology development. This paper provides an overview of the application of the ontology within the ACGT project thus far

Ontology Based Integration of Distributed and Heterogeneous Data Sources in ACGT.

In this work, we describe the set of tools comprising the Data Access Infrastructure within Advancing Clinic-genomic Trials on Cancer (ACGT), a R&D Project funded in part by the European. This infrastructure aims at improving Post-genomic clinical trials by providing seamless access to integrated clinical, genetic, and image databases. A data access layer, based on OGSA-DAI, has been developed in order to cope with syntactic heterogeneities in databases. The semantic problems present in data sources with different nature are tackled by two core tools, namely the Semantic Mediator and the Master Ontology on Cancer. The ontology is used as a common framework for semantics, modeling the domain and acting as giving support to homogenization. SPARQL has been selected as query language for the Data Access Services and the Mediator. Two experiments have been carried out in order to test the suitability of the selected approach, integrating clinical and DICOM image databases

A semantic interoperability approach to support integration of gene expression and clinical data in breast cancer

[Abstract] Introduction. The introduction of omics data and advances in technologies involved in clinical treatment has led to a broad range of approaches to represent clinical information. Within this context, patient stratification across health institutions due to omic profiling presents a complex scenario to carry out multi-center clinical trials. Methods. This paper presents a standards-based approach to ensure semantic integration required to facilitate the analysis of clinico-genomic clinical trials. To ensure interoperability across different institutions, we have developed a Semantic Interoperability Layer (SIL) to facilitate homogeneous access to clinical and genetic information, based on different well-established biomedical standards and following International Health (IHE) recommendations. Results. The SIL has shown suitability for integrating biomedical knowledge and technologies to match the latest clinical advances in healthcare and the use of genomic information. This genomic data integration in the SIL has been tested with a diagnostic classifier tool that takes advantage of harmonized multi-center clinico-genomic data for training statistical predictive models. Conclusions. The SIL has been adopted in national and international research initiatives, such as the EURECA-EU research project and the CIMED collaborative Spanish project, where the proposed solution has been applied and evaluated by clinical experts focused on clinico-genomic studies.Instituto de Salud Carlos III, PI13/02020Instituto de Salud Carlos III, PI13/0028

TumorML: Concept and requirements of an in silico cancer modelling markup language

This paper describes the initial groundwork carried out as part of the European Commission funded Transatlantic Tumor Model Repositories project, to develop a new markup language for computational cancer modelling, TumorML. In this paper we describe the motivations for such a language, arguing that current state-of-the-art biomodelling languages are not suited to the cancer modelling domain. We go on to describe the work that needs to be done to develop TumorML, the conceptual design, and a description of what existing markup languages will be used to compose the language specification

Developing a European grid infrastructure for cancer research: vision, architecture and services

Life sciences are currently at the centre of an information revolution. The nature and amount of information now available opens up areas of research that were once in the realm of science fiction. During this information revolution, the data-gathering capabilities have greatly surpassed the data-analysis techniques. Data integration across heterogeneous data sources and data aggregation across different aspects of the biomedical spectrum, therefore, is at the centre of current biomedical and pharmaceutical R&D

Digital Scientific Practice in Systems Medicine

The development of systems medicine has only been possible through the application of Information and Communication Technology (ICT) to handle the large volume and variety of data on health and disease. High-capacity databases and infrastructures based on ICT were established to support systematization and integration of data about complex physiological and pathological processes in cells and organisms. Although such infrastructures are essential for research and collaboration, they are often not regarded as being an integral part of the knowledge production itself. On the contrary, we argue that ICT is not only a science-supporting technology, but is deeply engraved in its scientific practices of knowledge generation. Findings supporting our argument are derived from an empirical case study in which we analysed the complex and dynamic relationship between systems medicine and information technology. The case under study was an international research project in which an integrated European ICT infrastructure was designed and developed in support of the systems oriented research community in oncology. By tracing the specific ways that systems medicine research produces, stores, and manages data in an ICT environment, this paper discusses the impact of ICT employed and to assess the consequences it may have for the process of knowledge production in systems medicine

Clinical Molecular Marker Testing Data Capture to Promote Precision Medicine Research Within the Cancer Research Network

PURPOSE: To evaluate health care systems for the availability of population-level data on the frequency of use and results of clinical molecular marker tests to inform precision cancer care. METHODS: We assessed cancer-related molecular marker test data availability across 12 US health care systems in the Cancer Research Network. Overall, these systems provide care to a diverse population of more than 12 million people in the United States. We performed qualitative analyses of test data availability for five blood-based protein, nine germline, and 14 tissue-based tumor marker tests in each health care system\u27s electronic health record and tumor registry using key informants, test code lists, and manual review of data types and output. We then performed quantitative analyses to estimate the proportion of patients with cancer with test utilization data and results for specific molecular marker tests. RESULTS: Health systems were able to systematically capture population-level data on all five blood protein markers, six of 14 tissue-based tumor markers, and none of the nine germline markers. Successful, systematic data capture was achievable for tests with electronic data feeds for test results (blood protein markers) or through prior manual abstraction by tumor registrars (select tumor-based markers). For test results stored in scanned image files (particularly germline and tumor marker tests), information on which test was performed and test results was not readily accessible in an electronic format. CONCLUSION: Even in health care systems with sophisticated electronic health records, there were few codified data elements available for evaluating precision cancer medicine test use and results at the population level. Health care organizations should establish standards for electronic reporting of precision medicine tests to expedite cancer research and facilitate the implementation of precision medicine approaches

An ontology to standardize research output of nutritional epidemiology : from paper-based standards to linked content

Background: The use of linked data in the Semantic Web is a promising approach to add value to nutrition research. An ontology, which defines the logical relationships between well-defined taxonomic terms, enables linking and harmonizing research output. To enable the description of domain-specific output in nutritional epidemiology, we propose the Ontology for Nutritional Epidemiology (ONE) according to authoritative guidance for nutritional epidemiology. Methods: Firstly, a scoping review was conducted to identify existing ontology terms for reuse in ONE. Secondly, existing data standards and reporting guidelines for nutritional epidemiology were converted into an ontology. The terms used in the standards were summarized and listed separately in a taxonomic hierarchy. Thirdly, the ontologies of the nutritional epidemiologic standards, reporting guidelines, and the core concepts were gathered in ONE. Three case studies were included to illustrate potential applications: (i) annotation of existing manuscripts and data, (ii) ontology-based inference, and (iii) estimation of reporting completeness in a sample of nine manuscripts. Results: Ontologies for food and nutrition (n = 37), disease and specific population (n = 100), data description (n = 21), research description (n = 35), and supplementary (meta) data description (n = 44) were reviewed and listed. ONE consists of 339 classes: 79 new classes to describe data and 24 new classes to describe the content of manuscripts. Conclusion: ONE is a resource to automate data integration, searching, and browsing, and can be used to assess reporting completeness in nutritional epidemiology

Precision Medicine: From Science To Value.

Precision medicine is making an impact on patients, health care delivery systems, and research participants in ways that were only imagined fifteen years ago when the human genome was first sequenced. Discovery of disease-causing and drug-response genetic variants has accelerated, while adoption into clinical medicine has lagged. We define precision medicine and the stakeholder community required to enable its integration into research and health care. We explore the intersection of data science, analytics, and precision medicine in the formation of health systems that carry out research in the context of clinical care and that optimize the tools and information used to deliver improved patient outcomes. We provide examples of real-world impact and conclude with a policy and economic agenda necessary for the adoption of this new paradigm of health care both in the United States and globally

Molecular Characterization and Novel Therapeutic Approaches in Hepatocellular Carcinoma

[eng] 1. HYPOTHESES Primary liver cancer is the sixth most commonly diagnosed cancer and the second leading cause of cancer-related death worldwide2,3. Around 90% of cases correspond to hepatocellular carcinoma (HCC)2,3, which arises almost unfailingly in the setting of chronic liver diseases. The worldwide incidence of HCC cases is heterogeneous, reflecting the distribution of risk factors, with Mongolia exhibiting the highest HCC burden worldwide2. Well-established HCC risk factors are hepatitis B virus, hepatitis C virus, and non-alcoholic fatty liver disease (NAFLD). Other agents have also been reported to promote hepatocarcinogenesis, including adeno-associated virus (AAV) integration3,4, but more studies are needed to determine in which conditions this virus can induce HCC. Approximately, 50–60% of HCC patients are exposed to systemic therapies in their lifespan, particularly in advanced stages of the disease3. These mostly include multikinase inhibitors such as lenvatinib and immune checkpoint inhibitors (ICI) such as anti-PD1 antibodies. Although ICIs are revolutionizing HCC treatment, monotherapy approaches elicit responses in only 15% of patients, while the majority are primarily resistant5,6. Thus, identifying existing multikinase inhibitors that can effectively synergize with ICI is urgently needed. During the last decade, molecular profiling of tumors using translational approaches has significantly contributed to the understanding of the molecular pathogenesis of HCC3,83. This knowledge has provided important opportunities in clinical oncology by 1) identifying novel genetic and environmental features associated with hepatocarcinogenesis in specific patient populations; and 2) unraveling new treatment strategies. Considering all this, the hypotheses of this thesis are that: 1. Performing a comprehensive analysis of the molecular and immunological features of HCC will provide relevant information about the genetic and molecular determinants associated with HCC in specific populations and will unveil novel potential therapeutic approaches. This could result in fundamental implications for the clinical decision- making in HCC. 2. Assessing the distinct genomic and transcriptomic alterations of Mongolian HCC could provide relevant information that may help unveil the genetic factors and environmental exposures underlying the high incidence in this population. 67 HYPOTHESES AND AIMS 3. Hepatocyte replication in response to liver injury and NAFLD could promote oncogenic AAV integration and HCC development, which could be a concern for the use of AAV gene therapy in patients with chronic liver. 4. The multikinase inhibitor lenvatinib has immune-modulating potential and its combination with anti-PD1 checkpoint inhibitors could improve its anti-tumoral effect in HCC. 2. AIMS. Considering the background and hypotheses exposed above, the specific aims of this doctoral thesis were the following: 1. To provide a molecular characterization of Mongolian HCC and identify its unique genomic features compared to Western HCC. 2. To assess whether NAFLD-associated liver damage increase the risk of AAV integration inducing HCC. 3. To identify the immunomodulatory effects of lenvatinib in combination with anti-PD1 and provide a mechanistic rationale for this treatment in advanced HCC.[cat] INTRODUCCIÓ: El carcinoma hepatocel·lular (CHC) representa un important problema de salut pública degut a la seva elevada incidència i mortalitat1,2. La incidència mundial de CHC és heterogènia, sent Mongòlia el país amb més casos per habitant, gairebé 10 vegades per sobre de la mitjana global2. Els principals factors de risc del CHC són la infecció pel virus de l'hepatitis B o pel virus de l'hepatitis C i la malaltia del fetge gras no alcohòlica (NAFLD, de les seves sigles en anglès). També s’han proposat altres agents que podrien estar associats a hepatocarcinogènesi, inclosa la infecció per virus adenoassociat (VAA)3,4, però és necessària més informació per determinar en quines condicions aquest virus pot promoure el CHC. Al voltant del 40% dels pacients amb CHC són diagnosticats en etapes avançades de la malaltia, en les quals són elegibles per a teràpies sistèmiques incloent inhibidors multiquinases (p. ex., lenvatinib) i inhibidors de punts de control immunitaris (ICI; p. ex., anticossos anti-PD1). Tot i que els ICI estan revolucionant el tractament del CHC, només aconsegueixen respostes en el ~15% dels pacients en monoteràpia5,6. Per contra, noves teràpies combinades estan incrementant la taxa de resposta fins al ~30%. Considerant això, és necessari identificar noves teràpies que puguin fer sinergia amb ICI per tal d’augmentar la supervivència dels pacients. Durant els últims anys, la caracterització molecular i immunològica de tumors mitjançant estudis translacionals ha proporcionat una millor comprensió de la patogènesi molecular del CHC5,6. Aquest coneixement té una gran rellevància clínica, ja que, entre altres coses, permet 1) identificar determinants genètics i moleculars que afavoreixen l'hepatocarcinogènesi en poblacions específiques de pacients; i 2) dissenyar nous tractaments incloent teràpies combinades. HIPÒTESIS: Les hipòtesis d’aquesta tesi són les següents: - L’anàlisi exhaustiva de les característiques moleculars i immunològiques del CHC proporcionarà nova informació sobre els determinants genètics i moleculars associats al CHC en poblacions d’alt risc, afavorint l’estudi de noves estratègies terapèutiques. Aquestes dades podrien tenir implicacions fonamentals per a la presa de decisions clíniques en CHC. - L'avaluació de les alteracions genòmiques i transcripcionals del CHC a Mongòlia pot proporcionar nova informació que ajudi a identificar factors genètics i ambientals propis associats a l’elevada incidència en aquesta població. - La malaltia hepàtica crònica i NAFLD promouen la integració oncogènica del VAA i el desenvolupament de CHC, la qual cosa podria ser un condicionant per a l'ús de la teràpia gènica mitjançant VAA en pacients. - L'inhibidor multiquinasa lenvatinib té potencial immunomodulador i la seva combinació amb ICI anti-PD1 podria incrementar l’efecte anti-tumoral en models experimentals i en pacients amb CHC. OBJECTIUS: Els objectius específics d'aquesta tesi doctoral són: - Realitzar una caracterització molecular del CHC a Mongòlia i identificar trets moleculars específics en comparació amb tumors de pacients occidentals. - Analitzar si el NAFLD incrementa el risc d’integració del VAA en hepatòcits, induint així el CHC. - Investigar l'efecte immunomodulador de lenvatinib en combinació amb l'anticòs anti-PD1 per proporcionar una base racional pel seu ús com a tractament pel CHC avançat. MÈTODES: - Estudi #1 (Torrens et al., en revisió): Un total de 192 mostres de tumors hepàtics CHC de pacients provinents de Mongòlia i 187 mostres de CHC de pacients occidentals (Europa i EEUU) van ser analitzades mitjançant seqüenciació completa d'exoma i d’ARN. Per identificar les característiques moleculars úniques del CHC de Mongòlia, es van comparar les característiques clinico-patològiques dels tumors de pacients mongols i occidentals, així com els seus perfils mutacionals i transcripcionals. - Estudi #2 (Dalwadi et al., Mol Ther 2021): Per tal de determinar si la infecció pel virus VAA dels hepatòcis promou l’hepatocarcinogènesi en condicions de malaltia hepàtica, es va fer servir un model animal murí on ratolins adults i nounats de la soca C57BL/6 van ser infectats amb un vector VAA dirigit contra el locus genètic Rian (VAA-Rian). A continuació, els animals van ser a) alimentats amb una dieta rica en greixos per generar NAFLD o b) sotmesos a hepatectomia parcial per generar dany hepàtic i regeneració. Es va monitoritzar el desenvolupament tumoral i els tumors generats es van caracteritzar mitjançant seqüenciació d'ARN. - Estudi #3 (Torrens et al., Hepatology 2021): Per avaluar l'activitat anti-tumoral de la combinació de l’inhibidor multiquinasa lenvatinib amb anti-PD1 es van generar tres models murins singènics de CHC. L’impacte dels tractaments sobre el perfil molecular i immunitari dels tumors van ser analitzats per citometria de flux i perfilats a nivell transcripcional i immunohistoquímic. Finalment, es va explorar el perfil d'expressió gènica de 228 tumors humans per identificar pacients amb CHC que es podrien beneficiar de la teràpia combinada de lenvatinib i anti-PD1. RESULTATS: - Estudi #1 (Torrens et al., en revisió): Els resultats del nostre estudi indiquen que els tumors CHC de pacients de Mongòlia presenten les següents particularitats: 1. Una elevada taxa de mutacions, que gairebé dobla la taxa de mutacions de la cohort occidental (121 davant de 70 mutacions per tumor). 2. Un perfil mutacional diferent, amb una major freqüència de mutacions de TP53, APOB, TSC2 i la família de gens KMT2. 3. La presència d'una nova firma mutacional (SBS Mongòlia) al 25% dels casos, que està associada a la firma del genotòxic dimetil sulfat derivat de la combustió del carbó. 4. A nivell d’expressió gènica, els tumors de la cohort de Mongòlia es classifiquen en tres classes moleculars (MGL1, MGL2 i MGL3), dues de les quals (MGL2 al 26% dels CHC i MGL3 al 30%) i presenten característiques moleculars i clínico-patològiques no observades en mostres de CHC occidental. - Estudi #2 (Dalwadi et al., Mol Ther 2021): 1. Només el 5% dels ratolins adults infectats amb VAA-Rian van desenvolupar CHC. Per contra, l’elevada proliferació cel·lular en nounats va promoure un increment en la integració viral i generació de tumors en el 100% dels animals. 2. Tant la lesió hepàtica per la dieta rica en greix com la derivada de l’hepatectomia parcial van conduir a un increment en l’aparició de CHC en ratolins adults infectats amb VAA-Rian en comparació amb animals infectats però no sotmesos a estrès hepàtic. 3. L'anàlisi transcriptòmica de tumors de CHC murins de ratolins originats degut a la infecció amb VAA-Rian va revelar similituds moleculars amb tumors de CHC humans amb sobreexpressió del locus Rian, associats amb proliferació, fenotip agressiu i mal pronòstic. 4. El fetge de ratolins alimentats amb una dieta rica en greixos presentaven un perfil immunològic protumorigènic, que podria ser el motiu de l’increment del risc de CHC induït per la infecció de VAA. - Estudi #3 (Torrens et al., Hepatology 2021): 1. La combinació de lenvatinib i anti-PD1 aconsegueix una major taxa de resposta, un temps de resposta més curt i una reducció de la viabilitat del tumor en comparació amb els tractaments administrats en monoteràpia. 2. Lenvatinib exerceix un potent efecte immunomodulador sobre l'infiltrat tumoral caracteritzat per una reducció en la proporció de cèl·lules T reguladores i inhibició de la senyalització immunosupressora mitjançant TGFß. 3. El tractament anti-PD1 modifica l'infiltrat immunològic del tumor augmentant les cèl·lules T i la subpoblació de cèl·lules dendrítiques de tipus 1 al tumor. 4. La combinació de lenvatinib amb anti-PD1 és l’únic dels tractaments avaluats capaç de generar una resposta immune anti-tumoral activada. 5. El 22% dels pacients amb CHC presenten un perfil transcripcional que podria estar associat a resistència primària a anti-PD1 i resposta al règim combinat. Aquests pacients podrien beneficiar-se de l'efecte de reforç del tractament de combinació. CONCLUSIONS: - El CHC a Mongòlia presenta característiques moleculars úniques comparat amb els tumors de pacients occidentals. El seu perfil mutacional podria ser degut a exposició a factors ambientals responsables de l'elevada incidència en aquest país. - La infecció amb el virus VAA promou el desenvolupament de CHC en models murins amb fetge gras degut a un augment en la proliferació d’hepatòcits i a la presència d'un infiltrat protumorogènic. Per tant, la teràpia gènica amb VAA podria resultar oncogènica en pacients amb inflamació hepàtica crònica. - La combinació de lenvatinib i anti-PD1 té un efecte immunomodulador al CHC caracteritzat per la generació d’un perfil immunològic activat. Aquest tractament podria maximitzar el benefici clínic en un subgrup de pacients de CHC. - Els estudis translacionals basats en models preclínics i anàlisis òmiques tenen la capacitat de revelar les característiques moleculars del CHC, potencials factors de risc i nous enfocaments terapèutics