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1.
Nat Commun ; 11(1): 729, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-32024854

RESUMO

The catalog of cancer driver mutations in protein-coding genes has greatly expanded in the past decade. However, non-coding cancer driver mutations are less well-characterized and only a handful of recurrent non-coding mutations, most notably TERT promoter mutations, have been reported. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2658 cancer across 38 tumor types, we perform multi-faceted pathway and network analyses of non-coding mutations across 2583 whole cancer genomes from 27 tumor types compiled by the ICGC/TCGA PCAWG project that was motivated by the success of pathway and network analyses in prioritizing rare mutations in protein-coding genes. While few non-coding genomic elements are recurrently mutated in this cohort, we identify 93 genes harboring non-coding mutations that cluster into several modules of interacting proteins. Among these are promoter mutations associated with reduced mRNA expression in TP53, TLE4, and TCF4. We find that biological processes had variable proportions of coding and non-coding mutations, with chromatin remodeling and proliferation pathways altered primarily by coding mutations, while developmental pathways, including Wnt and Notch, altered by both coding and non-coding mutations. RNA splicing is primarily altered by non-coding mutations in this cohort, and samples containing non-coding mutations in well-known RNA splicing factors exhibit similar gene expression signatures as samples with coding mutations in these genes. These analyses contribute a new repertoire of possible cancer genes and mechanisms that are altered by non-coding mutations and offer insights into additional cancer vulnerabilities that can be investigated for potential therapeutic treatments.

2.
Bioinformatics ; 2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31722383

RESUMO

Supplementary data are available at Bioinformatics online.

3.
PLoS Comput Biol ; 15(10): e1007291, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31622330

RESUMO

As with many other aspects of the modern world, in healthcare, the explosion of data and resources opens new opportunities for the development of added-value services. Still, a number of specific conditions on this domain greatly hinders these developments, including ethical and legal issues, fragmentation of the relevant data in different locations, and a level of (meta)data complexity that requires great expertise across technical, clinical, and biological domains. We propose the Patient Dossier paradigm as a way to organize new innovative healthcare services that sorts the current limitations. The Patient Dossier conceptual framework identifies the different issues and suggests how they can be tackled in a safe, efficient, and responsible way while opening options for independent development for different players in the healthcare sector. An initial implementation of the Patient Dossier concepts in the Rbbt framework is available as open-source at https://github.com/mikisvaz and https://github.com/Rbbt-Workflows.

5.
Genome Biol ; 20(1): 164, 2019 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-31405382

RESUMO

Bioinformaticians and biologists rely increasingly upon workflows for the flexible utilization of the many life science tools that are needed to optimally convert data into knowledge. We outline a pan-European enterprise to provide a catalogue ( https://bio.tools ) of tools and databases that can be used in these workflows. bio.tools not only lists where to find resources, but also provides a wide variety of practical information.


Assuntos
Disciplinas das Ciências Biológicas , Bases de Dados Factuais , Software , Internet
6.
Nat Rev Genet ; 20(11): 693-701, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31455890

RESUMO

Human genomics is undergoing a step change from being a predominantly research-driven activity to one driven through health care as many countries in Europe now have nascent precision medicine programmes. To maximize the value of the genomic data generated, these data will need to be shared between institutions and across countries. In recognition of this challenge, 21 European countries recently signed a declaration to transnationally share data on at least 1 million human genomes by 2022. In this Roadmap, we identify the challenges of data sharing across borders and demonstrate that European research infrastructures are well-positioned to support the rapid implementation of widespread genomic data access.

7.
Bioinformatics ; 35(22): 4846-4848, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31173067

RESUMO

MOTIVATION: Genetic alterations lead to tumor progression and cell survival but also uncover cancer-specific vulnerabilities on gene dependencies that can be therapeutically exploited. RESULTS: vulcanSpot is a novel computational approach implemented to expand the therapeutic options in cancer beyond known-driver genes unlocking alternative ways to target undruggable genes. The method integrates genome-wide information provided by massive screening experiments to detect genetic vulnerabilities associated to tumors. Then, vulcanSpot prioritizes drugs to target cancer-specific gene dependencies using a weighted scoring system based on well known drug-gene relationships and drug repositioning strategies. AVAILABILITY AND IMPLEMENTATION: http://www.vulcanspot.org. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

8.
JAMA Netw Open ; 2(6): e195313, 2019 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-31173122

RESUMO

Importance: Anorexia nervosa is recognized as an important cause of morbidity in young people. However, the risk of cancer in people with anorexia nervosa remains uncertain. Objective: To evaluate the association of anorexia nervosa with the risk of developing or dying of cancer. Data Sources: MEDLINE, Scopus, Embase, and Web of Science from database inception to January 9, 2019. Study Selection: Published observational studies in humans examining the risk of cancer in people with anorexia nervosa compared with the general population or those without anorexia nervosa. Studies needed to report incidence or mortality rate ratios (RRs). Data Extraction and Synthesis: Screening, data extraction, and methodological quality assessment were performed by at least 2 researchers independently. A random-effects model was used to synthesize individual studies. Heterogeneity (I2) was assessed and 95% prediction intervals (PIs) were calculated. Main Outcomes and Measures: All cancer incidence and cancer mortality associated with anorexia nervosa. Secondary outcomes were site-specific cancer incidence and mortality. Results: Seven cohort studies published in 10 articles (42 602 participants with anorexia nervosa) were included. Anorexia nervosa was not associated with risk of developing any cancer (4 studies in women; RR, 0.97; 95% CI, 0.89-1.06; P = .53; I2, 0%; 95% PI, 0.80-1.18; moderate confidence). Anorexia nervosa was associated with decreased breast cancer incidence (5 studies in women; RR, 0.60; 95% CI, 0.50-0.80; P < .001; I2, 0%; 95% PI, 0.44-0.83; high confidence). Conversely, anorexia nervosa was associated with increased risk of developing lung cancer (3 studies in women; RR, 1.50; 95% CI, 1.06-2.12; P = .001; I2, 0%; 95% PI, 0.19-16.46; low confidence) and esophageal cancer (2 studies in women; RR, 6.10; 95% CI, 2.30-16.18; P < .001; I2, 0%; low confidence). Conclusions and Relevance: Among people with anorexia nervosa, risk of developing cancer did not differ compared with the general population, but a significantly reduced risk of breast cancer was observed. Understanding the mechanisms underlying these associations could have important preventive potential.

9.
J Cheminform ; 11(1): 42, 2019 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-31236786

RESUMO

BACKGROUND: Shared tasks and community challenges represent key instruments to promote research, collaboration and determine the state of the art of biomedical and chemical text mining technologies. Traditionally, such tasks relied on the comparison of automatically generated results against a so-called Gold Standard dataset of manually labelled textual data, regardless of efficiency and robustness of the underlying implementations. Due to the rapid growth of unstructured data collections, including patent databases and particularly the scientific literature, there is a pressing need to generate, assess and expose robust big data text mining solutions to semantically enrich documents in real time. To address this pressing need, a novel track called "Technical interoperability and performance of annotation servers" was launched under the umbrella of the BioCreative text mining evaluation effort. The aim of this track was to enable the continuous assessment of technical aspects of text annotation web servers, specifically of online biomedical named entity recognition systems of interest for medicinal chemistry applications. RESULTS: A total of 15 out of 26 registered teams successfully implemented online annotation servers. They returned predictions during a two-month period in predefined formats and were evaluated through the BeCalm evaluation platform, specifically developed for this track. The track encompassed three levels of evaluation, i.e. data format considerations, technical metrics and functional specifications. Participating annotation servers were implemented in seven different programming languages and covered 12 general entity types. The continuous evaluation of server responses accounted for testing periods of low activity and moderate to high activity, encompassing overall 4,092,502 requests from three different document provider settings. The median response time was below 3.74 s, with a median of 10 annotations/document. Most of the servers showed great reliability and stability, being able to process over 100,000 requests in a 5-day period. CONCLUSIONS: The presented track was a novel experimental task that systematically evaluated the technical performance aspects of online entity recognition systems. It raised the interest of a significant number of participants. Future editions of the competition will address the ability to process documents in bulk as well as to annotate full-text documents.

10.
Int J Mol Sci ; 20(13)2019 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-31247897

RESUMO

Matrix factorization (MF) is an established paradigm for large-scale biological data analysis with tremendous potential in computational biology. Here, we challenge MF in depicting the molecular bases of epidemiologically described disease-disease (DD) relationships. As a use case, we focus on the inverse comorbidity association between Alzheimer's disease (AD) and lung cancer (LC), described as a lower than expected probability of developing LC in AD patients. To this day, the molecular mechanisms underlying DD relationships remain poorly explained and their better characterization might offer unprecedented clinical opportunities. To this goal, we extend our previously designed MF-based framework for the molecular characterization of DD relationships. Considering AD-LC inverse comorbidity as a case study, we highlight multiple molecular mechanisms, among which we confirm the involvement of processes related to the immune system and mitochondrial metabolism. We then distinguish mechanisms specific to LC from those shared with other cancers through a pan-cancer analysis. Additionally, new candidate molecular players, such as estrogen receptor (ER), cadherin 1 (CDH1) and histone deacetylase (HDAC), are pinpointed as factors that might underlie the inverse relationship, opening the way to new investigations. Finally, some lung cancer subtype-specific factors are also detected, also suggesting the existence of heterogeneity across patients in the context of inverse comorbidity.


Assuntos
Doença de Alzheimer/epidemiologia , Biologia Computacional , Neoplasias Pulmonares/epidemiologia , Modelos Biológicos , Algoritmos , Doença de Alzheimer/complicações , Doença de Alzheimer/etiologia , Comorbidade , Biologia Computacional/métodos , Humanos , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/etiologia
11.
Mol Autism ; 10: 17, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31007884

RESUMO

Background: Epidemiological and clinical evidence points to cancer as a comorbidity in people with autism spectrum disorders (ASD). A significant overlap of genes and biological processes between both diseases has also been reported. Methods: Here, for the first time, we compared the gene expression profiles of ASD frontal cortex tissues and 22 cancer types obtained by differential expression meta-analysis and report gene, pathway, and drug set-based overlaps between them. Results: Four cancer types (brain, thyroid, kidney, and pancreatic cancers) presented a significant overlap in gene expression deregulations in the same direction as ASD whereas two cancer types (lung and prostate cancers) showed differential expression profiles significantly deregulated in the opposite direction from ASD. Functional enrichment and LINCS L1000 based drug set enrichment analyses revealed the implication of several biological processes and pathways that were affected jointly in both diseases, including impairments of the immune system, and impairments in oxidative phosphorylation and ATP synthesis among others. Our data also suggest that brain and kidney cancer have patterns of transcriptomic dysregulation in the PI3K/AKT/MTOR axis that are similar to those found in ASD. Conclusions: Comparisons of ASD and cancer differential gene expression meta-analysis results suggest that brain, kidney, thyroid, and pancreatic cancers are candidates for direct comorbid associations with ASD. On the other hand, lung and prostate cancers are candidates for inverse comorbid associations with ASD. Joint perturbations in a set of specific biological processes underlie these associations which include several pathways previously implicated in both cancer and ASD encompassing immune system alterations, impairments of energy metabolism, cell cycle, and signaling through PI3K and G protein-coupled receptors among others. These findings could help to explain epidemiological observations pointing towards direct and inverse comorbid associations between ASD and specific cancer types and depict a complex scenario regarding the molecular patterns of association between ASD and cancer.


Assuntos
Transtorno Autístico/genética , Encéfalo/metabolismo , Neoplasias/genética , Transcriptoma , Transtorno Autístico/epidemiologia , Humanos , Neoplasias/epidemiologia , Transdução de Sinais/genética
12.
Curr Opin Biotechnol ; 58: 161-167, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30965188

RESUMO

Big Data are radically changing biomedical research. The unprecedented advances in automated collection of large-scale molecular and clinical data pose major challenges to data analysis and interpretation, calling for the development of new computational approaches. The creation of powerful systems for the effective use of biomedical Big Data in Personalized Medicine (a.k.a. Precision Medicine) will require significant scientific and technical developments, including infrastructure, engineering, project and financial management. We review here how the evolution of data-driven methods offers the possibility to address many of these problems, guiding the formulation of hypotheses on systems functioning and the generation of mechanistic models, and facilitating the design of clinical procedures in Personalized Medicine.

13.
PLoS Genet ; 15(1): e1007902, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30677042

RESUMO

Introns can be extraordinarily large and they account for the majority of the DNA sequence in human genes. However, little is known about their population patterns of structural variation and their functional implication. By combining the most extensive maps of CNVs in human populations, we have found that intronic losses are the most frequent copy number variants (CNVs) in protein-coding genes in human, with 12,986 intronic deletions, affecting 4,147 genes (including 1,154 essential genes and 1,638 disease-related genes). This intronic length variation results in dozens of genes showing extreme population variability in size, with 40 genes with 10 or more different sizes and up to 150 allelic sizes. Intronic losses are frequent in evolutionarily ancient genes that are highly conserved at the protein sequence level. This result contrasts with losses overlapping exons, which are observed less often than expected by chance and almost exclusively affect primate-specific genes. An integrated analysis of CNVs and RNA-seq data showed that intronic loss can be associated with significant differences in gene expression levels in the population (CNV-eQTLs). These intronic CNV-eQTLs regions are enriched for intronic enhancers and can be associated with expression differences of other genes showing long distance intron-promoter 3D interactions. Our data suggests that intronic structural variation of protein-coding genes makes an important contribution to the variability of gene expression and splicing in human populations.


Assuntos
Variações do Número de Cópias de DNA/genética , Evolução Molecular , Genética Populacional , Locos de Características Quantitativas/genética , Alelos , Éxons/genética , Dosagem de Genes/genética , Regulação da Expressão Gênica , Genoma Humano/genética , Humanos , Íntrons/genética , Processamento de RNA/genética
16.
Brief Bioinform ; 20(3): 752-766, 2019 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-29077790

RESUMO

Success in precision medicine depends on accessing high-quality genetic and molecular data from large, well-annotated patient cohorts that couple biological samples to comprehensive clinical data, which in conjunction can lead to effective therapies. From such a scenario emerges the need for a new professional profile, an expert bioinformatician with training in clinical areas who can make sense of multi-omics data to improve therapeutic interventions in patients, and the design of optimized basket trials. In this review, we first describe the main policies and international initiatives that focus on precision medicine. Secondly, we review the currently ongoing clinical trials in precision medicine, introducing the concept of 'precision bioinformatics', and we describe current pioneering bioinformatics efforts aimed at implementing tools and computational infrastructures for precision medicine in health institutions around the world. Thirdly, we discuss the challenges related to the clinical training of bioinformaticians, and the urgent need for computational specialists capable of assimilating medical terminologies and protocols to address real clinical questions. We also propose some skills required to carry out common tasks in clinical bioinformatics and some tips for emergent groups. Finally, we explore the future perspectives and the challenges faced by precision medicine bioinformatics.

17.
Bioinformatics ; 35(14): 2518-2520, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-30521012

RESUMO

MOTIVATION: The fast growth of bioinformatics adds a significant difficulty to assess the contribution, geographical and thematic distribution of the research publications. RESULTS: To help researchers, grant agencies and general public to assess the progress in bioinformatics, we have developed BIOLITMAP, a web-based geolocation system that allows an easy and sensible exploration of the publications by institution, year and topic. AVAILABILITY AND IMPLEMENTATION: BIOLITMAP is available at http://socialanalytics.bsc.es/biolitmap and the sources have been deposited at https://github.com/inab/BIOLITMAP. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

18.
Cell Rep ; 24(10): 2784-2794, 2018 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-30184510

RESUMO

Neutrophils are short-lived blood cells that play a critical role in host defense against infections. To better comprehend neutrophil functions and their regulation, we provide a complete epigenetic overview, assessing important functional features of their differentiation stages from bone marrow-residing progenitors to mature circulating cells. Integration of chromatin modifications, methylation, and transcriptome dynamics reveals an enforced regulation of differentiation, for cellular functions such as release of proteases, respiratory burst, cell cycle regulation, and apoptosis. We observe an early establishment of the cytotoxic capability, while the signaling components that activate these antimicrobial mechanisms are transcribed at later stages, outside the bone marrow, thus preventing toxic effects in the bone marrow niche. Altogether, these data reveal how the developmental dynamics of the chromatin landscape orchestrate the daily production of a large number of neutrophils required for innate host defense and provide a comprehensive overview of differentiating human neutrophils.


Assuntos
Células da Medula Óssea/citologia , Células da Medula Óssea/metabolismo , Neutrófilos/citologia , Neutrófilos/metabolismo , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Cromatina/genética , Cromatina/metabolismo , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/fisiologia , Humanos
19.
Genome Med ; 10(1): 41, 2018 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-29848362

RESUMO

BACKGROUND: Large-sequencing cancer genome projects have shown that tumors have thousands of molecular alterations and their frequency is highly heterogeneous. In such scenarios, physicians and oncologists routinely face lists of cancer genomic alterations where only a minority of them are relevant biomarkers to drive clinical decision-making. For this reason, the medical community agrees on the urgent need of methodologies to establish the relevance of tumor alterations, assisting in genomic profile interpretation, and, more importantly, to prioritize those that could be clinically actionable for cancer therapy. RESULTS: We present PanDrugs, a new computational methodology to guide the selection of personalized treatments in cancer patients using the variant lists provided by genome-wide sequencing analyses. PanDrugs offers the largest database of drug-target associations available from well-known targeted therapies to preclinical drugs. Scoring data-driven gene cancer relevance and drug feasibility PanDrugs interprets genomic alterations and provides a prioritized evidence-based list of anticancer therapies. Our tool represents the first drug prescription strategy applying a rational based on pathway context, multi-gene markers impact and information provided by functional experiments. Our approach has been systematically applied to TCGA patients and successfully validated in a cancer case study with a xenograft mouse model demonstrating its utility. CONCLUSIONS: PanDrugs is a feasible method to identify potentially druggable molecular alterations and prioritize drugs to facilitate the interpretation of genomic landscape and clinical decision-making in cancer patients. Our approach expands the search of druggable genomic alterations from the concept of cancer driver genes to the druggable pathway context extending anticancer therapeutic options beyond already known cancer genes. The methodology is public and easily integratable with custom pipelines through its programmatic API or its docker image. The PanDrugs webtool is freely accessible at http://www.pandrugs.org .


Assuntos
Antineoplásicos/uso terapêutico , Biologia Computacional/métodos , Genômica , Neoplasias/tratamento farmacológico , Neoplasias/genética , Medicina de Precisão , Simulação por Computador , Genoma Humano , Humanos
20.
Hum Mutat ; 39(9): 1214-1225, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29900613

RESUMO

The causal association of NUDT1 (=MTH1) and OGG1 with hereditary colorectal cancer (CRC) remains unclear. Here, we sought to provide additional evidence for or against the causal contribution of NUDT1 and OGG1 mutations to hereditary CRC and/or polyposis. Mutational screening was performed using pooled DNA amplification and targeted next-generation sequencing in 529 families (441 uncharacterized MMR-proficient familial nonpolyposis CRC and 88 polyposis cases). Cosegregation, in silico analyses, in vitro functional assays, and case-control associations were carried out to characterize the identified variants. Five heterozygous carriers of novel (n = 1) or rare (n = 4) NUDT1 variants were identified. In vitro deleterious effects were demonstrated for c.143G>A p.G48E (catalytic activity and protein stability) and c.403G>T p.G135W (protein stability), although cosegregation data in the carrier families were inconclusive or nonsupportive. The frequency of missense, loss-of-function, and splice-site NUDT1 variants in our familial CRC cohort was similar to the one observed in cancer-free individuals, suggesting lack of association with CRC predisposition. No OGG1 pathogenic mutations were identified. Our results suggest that the contribution of NUDT1 and OGG1 germline mutations to hereditary CRC and to polyposis is inexistent or, at most, negligible. The inclusion of these genes in routine genetic testing is not recommended.


Assuntos
Polipose Adenomatosa do Colo/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , DNA Glicosilases/genética , Enzimas Reparadoras do DNA/genética , Monoéster Fosfórico Hidrolases/genética , Polipose Adenomatosa do Colo/patologia , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Reparo do DNA/genética , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Variação Genética/genética , Genótipo , Mutação em Linhagem Germinativa/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação com Perda de Função/genética , Masculino , Mutação de Sentido Incorreto/genética , Estresse Oxidativo , Isoformas de Proteínas/genética
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