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From cancer genomes to cancer models: bridging the gaps

Anaïs Baudot, Francisco X. Real, José M. G. Izarzugaza, Alfonso Valencia
2009 EMBO Reports  
ACKNOWLEDGEMENTS We thank M. Soengas and A. Toll for providing microphotographs.  ... 
doi:10.1038/embor.2009.46 pmid:19305388 pmcid:PMC2672900 fatcat:yfjgy6mcqvcjlf6g6nw4pwpwtu

Benchmarking the HLA typing performance of Polysolver and Optitype in 50 Danish parental trios

Maria Luisa Matey-Hernandez, Søren Brunak, Jose M. G. Izarzugaza
2018 BMC Bioinformatics  
The adaptive immune response intrinsically depends on hypervariable human leukocyte antigen (HLA) genes. Concomitantly, correct HLA phenotyping is crucial for successful donor-patient matching in organ transplantation. The cost and technical limitations of current laboratory techniques, together with advances in nextgeneration sequencing (NGS) methodologies, have increased the need for precise computational typing methods. Results: We tested two widespread HLA typing methods using high quality
more » ... ull genome sequencing data from 150 individuals in 50 family trios from the Genome Denmark project. First, we computed descendant accuracies assessing the agreement in the inheritance of alleles from parents to offspring. Second, we compared the locus-specific homozygosity rates as well as the allele frequencies; and we compared those to the observed values in related populations. We provide guidelines for testing the accuracy of HLA typing methods by comparing family information, which is independent of the availability of curated alleles. Conclusions: Although current computational methods for HLA typing generally provide satisfactory results, our benchmarkusing data with ultra-high sequencing depthdemonstrates the incompleteness of current reference databases, and highlights the importance of providing genomic databases addressing current sequencing standards, a problem yet to be resolved before benefiting fully from personalised medicine approaches HLA phenotyping is essential.
doi:10.1186/s12859-018-2239-6 pmid:29940840 pmcid:PMC6019707 fatcat:gtbu5mi7mvhnxeef2jajbsbday

Interpretation of the Consequences of Mutations in Protein Kinases: Combined Use of Bioinformatics and Text Mining

Jose M. G. Izarzugaza, Martin Krallinger, Alfonso Valencia
2012 Frontiers in Physiology  
Moreover, features can also either be general or apply only to a defined subset of proteins, as is the membership to a kinase group (Torkamani and Schork, 2007; Izarzugaza et al., 2012) .  ...  In addition to the predictions of pathogenicity directly from our in-house classifier (Izarzugaza et al., 2012) and the values of the features used in the classification, wKinMut combines information  ... 
doi:10.3389/fphys.2012.00323 pmid:23055974 pmcid:PMC3449330 fatcat:i2qqkuh4nfde3pxeknjbvgpfpe

Prediction of Disease Causing Non-Synonymous SNPs by the Artificial Neural Network Predictor NetDiseaseSNP

Morten Bo Johansen, Jose M. G. Izarzugaza, Søren Brunak, Thomas Nordahl Petersen, Ramneek Gupta, David K. Crockett
2013 PLoS ONE  
NetDiseaseSNP is publicly available as an online tool as well as a web service: Citation: Johansen MB, Izarzugaza JMG, Brunak S, Petersen TN, Gupta R (2013)  ... 
doi:10.1371/journal.pone.0068370 pmid:23935863 pmcid:PMC3723835 fatcat:the4duogpjbizo3guai2oyeu2a

Identification of hyper-rewired genomic stress non-oncogene addiction genes across 15 cancer types

Jessica Xin Hjaltelin, Jose M. G. Izarzugaza, Lars Juhl Jensen, Francesco Russo, David Westergaard, Søren Brunak
2019 npj Systems Biology and Applications  
Non-oncogene addiction (NOA) genes are essential for supporting the stress-burdened phenotype of tumours and thus vital for their survival. Although NOA genes are acknowledged to be potential drug targets, there has been no large-scale attempt to identify and characterise them as a group across cancer types. Here we provide the first method for the identification of conditional NOA genes and their rewired neighbours using a systems approach. Using copy number data and expression profiles from
more » ... e Cancer Genome Atlas (TCGA) we performed comparative analyses between high and low genomic stress tumours for 15 cancer types. We identified 101 condition-specific differential coexpression modules, mapped to a high-confidence human interactome, comprising 133 candidate NOA rewiring hub genes. We observe that most modules lose coexpression in the high-stress state and that activated stress modules and hubs take part in homoeostasis maintenance processes such as chromosome segregation, oxireductase activity, mitotic checkpoint (PLK1 signalling), DNA replication initiation and synaptic signalling. We furthermore show that candidate NOA rewiring hubs are unique for each cancer type, but that their respective rewired neighbour genes largely are shared across cancer types.
doi:10.1038/s41540-019-0104-5 pmid:31396397 pmcid:PMC6685999 fatcat:bcks4jkubrgbhgkot4i2rfoxui

A generic Deep Convolutional Neural Network framework for prediction of Receptor-ligand Interactions. NetPhosPan; Application to Kinase Phosphorylation prediction

Emilio Fenoy, Jose M G Izarzugaza, Vanessa Jurtz, Søren Brunak, Morten Nielsen, John Hancock
2018 Bioinformatics  
Motivation: Understanding the specificity of protein receptor-ligand interactions is pivotal for our comprehension of biological mechanisms and systems. Receptor protein families often have a certain level of sequence diversity that converges into fewer conserved protein structures, allowing the exertion of well-defined functions. T and B cell receptors of the immune system and protein kinases that control the dynamic behaviour and decision processes in eukaryotic cells by catalysing
more » ... tion represent prime examples. Driven by the large sequence diversity, the receptors within such protein families are often found to share specificities although divergent at the sequence level. This observation has led to the notion that prediction models of such systems are most effectively handled in a receptor-specific manner. Results: We show that this approach in many cases is suboptimal, and describe an alternative improved framework for generating models with pan-receptor predictive power for receptor protein families. The framework is based on deep artificial neural networks and integrates information from individual receptors into a single pan-receptor model, leveraging information across multiple receptor-specific data sets allowing predictions of the receptor specificity for all members of a given protein family including those described by limited or no ligand data. The approach was applied to the protein kinase superfamily, leading to the method NetPhosPan. The method was extensively validated and benchmarked against state-of-the-art prediction methods and was found to have unprecedented performance in particularly for kinase domains characterized by limited or no experimental data. Availability and Implementation: The method is freely available to non-commercial users and can be downloaded at
doi:10.1093/bioinformatics/bty715 pmid:30169744 fatcat:7mqjjpoh2nfbvolb2evrperbie

Retinoic Acid Signaling in Thymic Epithelial Cells Regulates Thymopoiesis

Kerstin Wendland, Kristoffer Niss, Knut Kotarsky, Nikita Y. H. Wu, Andrea J. White, Johan Jendholm, Aymeric Rivollier, Jose M. G. Izarzugaza, Søren Brunak, Georg A. Holländer, Graham Anderson, Katarzyna M. Sitnik (+1 others)
2018 Journal of Immunology  
Kirstine G. Belling (University of Copenhagen, Copenhagen, Denmark) for technical support and Ann-Charlotte Selberg (Lund University) for animal care and genotyping.  ...  (F) Representative flow cytometry plots mice and (G) percentage of killed target cells 4 h postinjection into OVA and anti-CD40-immunized mice. Data are from three experiments.  ... 
doi:10.4049/jimmunol.1800418 pmid:29848752 fatcat:75lt2cndv5a4lp4ejynf4pprj4

Single-cell characterisation of mononuclear phagocytes in the human intestinal mucosa [article]

Thomas M Fenton, Line Wulff, Gareth-Rhys Jones, Julien Vandamme, Peter B Jørgensen, Calum C Bain, Julie Lee, Jose MG Izarzugaza, Kirstine G Belling, Gwo-tzer Ho, Ole H Nielsen, Lene B Riis (+5 others)
2021 bioRxiv   pre-print
The suspension was passed through a 100 µm filter before washing twice in fresh media 701 and centrifuging to form a pellet. 702 703 Flow cytometry 704 Cell suspensions were stained with the antibodies  ...  G) Pseudotime score calculated as means of trajectories for each cDC cluster, starting in cluster D7, based on tSpace outputs.  ... 
doi:10.1101/2021.03.28.437379 fatcat:cqszblvecnfsvifvzkbzncfgiu

Tumor Mutation Burden Forecasts Outcome in Ovarian Cancer with BRCA1 or BRCA2 Mutations

Nicolai Juul Birkbak, Bose Kochupurakkal, Jose M. G. Izarzugaza, Aron C. Eklund, Yang Li, Joyce Liu, Zoltan Szallasi, Ursula A. Matulonis, Andrea L. Richardson, J. Dirk Iglehart, Zhigang C. Wang, Peiwen Fei
2013 PLoS ONE  
Increased number of single nucleotide substitutions is seen in breast and ovarian cancer genomes carrying disease-associated mutations in BRCA1 or BRCA2. The significance of these genome-wide mutations is unknown. We hypothesize genome-wide mutation burden mirrors deficiencies in DNA repair and is associated with treatment outcome in ovarian cancer. Methods and Results: The total number of synonymous and non-synonymous exome mutations (Nmut), and the presence of germline or somatic mutation in
more » ... RCA1 or BRCA2 (mBRCA) were extracted from whole-exome sequences of high-grade serous ovarian cancers from The Cancer Genome Atlas (TCGA). Cox regression and Kaplan-Meier methods were used to correlate Nmut with chemotherapy response and outcome. Higher Nmut correlated with a better response to chemotherapy after surgery. In patients with mBRCA-associated cancer, low Nmut was associated with shorter progression-free survival (PFS) and overall survival (OS), independent of other prognostic factors in multivariate analysis. Patients with mBRCA-associated cancers and a high Nmut had remarkably favorable PFS and OS. The association with survival was similar in cancers with either BRCA1 or BRCA2 mutations. In cancers with wild-type BRCA, tumor Nmut was associated with treatment response in patients with no residual disease after surgery. Conclusions: Tumor Nmut was associated with treatment response and with both PFS and OS in patients with highgrade serous ovarian cancer carrying BRCA1 or BRCA2 mutations. In the TCGA cohort, low Nmut predicted resistance to chemotherapy, and for shorter PFS and OS, while high Nmut forecasts a remarkably favorable outcome in mBRCA-associated ovarian cancer. Our observations suggest that the total mutation burden coupled with BRCA1 or BRCA2 mutations in ovarian cancer is a genomic marker of prognosis and predictor of treatment response. This marker may reflect the degree of deficiency in BRCA-mediated pathways, or the extent of compensation for the deficiency by alternative mechanisms.
doi:10.1371/journal.pone.0080023 pmid:24265793 pmcid:PMC3827141 fatcat:kion6eilnjadjjdoloheysnsqe

Propionibacterium acnes: Disease-Causing Agent or Common Contaminant? Detection in Diverse Patient Samples by Next-Generation Sequencing

Sarah Mollerup, Jens Friis-Nielsen, Lasse Vinner, Thomas Arn Hansen, Stine Raith Richter, Helena Fridholm, Jose Alejandro Romero Herrera, Ole Lund, Søren Brunak, Jose M. G. Izarzugaza, Tobias Mourier, Lars Peter Nielsen (+2 others)
2016 Journal of Clinical Microbiology  
subsequently filtered through 5-m-pore-size centrifuge filters (Millipore, Darmstadt, Germany).  ...  All tissue homogenates, samples from leukemia patients, and ascitic fluid specimens (1 ml) devoid of pelleted cells were centrifuged for 2 min at 800 ϫ g to remove tissue debris, and the supernatants were  ... 
doi:10.1128/jcm.02723-15 pmid:26818667 pmcid:PMC4809928 fatcat:k6apev6atfbbrenur4ywhv7jsi

Systems genetics analysis identifies calcium-signaling defects as novel cause of congenital heart disease

Jose M. G. Izarzugaza, Competence Network for Congenital Heart Defects, Germany, Sabrina G. Ellesøe, Canan Doganli, Natasja Spring Ehlers, Marlene D. Dalgaard, Enrique Audain, Gregor Dombrowsky, Karina Banasik, Alejandro Sifrim, Anna Wilsdon, Bernard Thienpont (+6 others)
2020 Genome Medicine  
Congenital heart disease (CHD) occurs in almost 1% of newborn children and is considered a multifactorial disorder. CHD may segregate in families due to significant contribution of genetic factors in the disease etiology. The aim of the study was to identify pathophysiological mechanisms in families segregating CHD. We used whole exome sequencing to identify rare genetic variants in ninety consenting participants from 32 Danish families with recurrent CHD. We applied a systems biology approach
more » ... o identify developmental mechanisms influenced by accumulation of rare variants. We used an independent cohort of 714 CHD cases and 4922 controls for replication and performed functional investigations using zebrafish as in vivo model. We identified 1785 genes, in which rare alleles were shared between affected individuals within a family. These genes were enriched for known cardiac developmental genes, and 218 of these genes were mutated in more than one family. Our analysis revealed a functional cluster, enriched for proteins with a known participation in calcium signaling. Replication in an independent cohort confirmed increased mutation burden of calcium-signaling genes in CHD patients. Functional investigation of zebrafish orthologues of ITPR1, PLCB2, and ADCY2 verified a role in cardiac development and suggests a combinatorial effect of inactivation of these genes. The study identifies abnormal calcium signaling as a novel pathophysiological mechanism in human CHD and confirms the complex genetic architecture underlying CHD.
doi:10.1186/s13073-020-00772-z pmid:32859249 pmcid:PMC7453558 fatcat:l7umx4jmjrf4hnlkb53borq6pm

Investigation of Human Cancers for Retrovirus by Low-Stringency Target Enrichment and High-Throughput Sequencing

Lasse Vinner, Tobias Mourier, Jens Friis-Nielsen, Robert Gniadecki, Karen Dybkaer, Jacob Rosenberg, Jill Levin Langhoff, David Flores Santa Cruz, Jannik Fonager, Jose M. G. Izarzugaza, Ramneek Gupta, Thomas Sicheritz-Ponten (+4 others)
2015 Scientific Reports  
In capture-enriched libraries, we detected as few as 91 copies of HIV-1 proviral DNA per μ g gDNA (Table 1) .  ...  We investigated target capture of varying quantities of proviral HIV-1 in gDNA from blood donors (1 μ g/reaction).  ... 
doi:10.1038/srep13201 pmid:26285800 pmcid:PMC4541070 fatcat:v5pxlzjs45cxjncqoat6its5c4

Pathway and network analysis of more than 2500 whole cancer genomes

Matthew A. Reyna, PCAWG Drivers and Functional Interpretation Working Group, David Haan, Marta Paczkowska, Lieven P. C. Verbeke, Miguel Vazquez, Abdullah Kahraman, Sergio Pulido-Tamayo, Jonathan Barenboim, Lina Wadi, Priyanka Dhingra, Raunak Shrestha (+16 others)
2020 Nature Communications  
GS-C: p C (g) = p coding (g) 2. GS-N: p N (g) = fisher(min(p promoter (g), p 5′UTR (g)), p 3′UTR (g), p enhancer (g)) 3.  ...  GS-CN: p CN (g) = fisher(p coding (g), min(p promoter (g), p 5′UTR (g)), p 3′UTR (g), p enhancer (g)).  ... 
doi:10.1038/s41467-020-14367-0 pmid:32024854 pmcid:PMC7002574 fatcat:n3r2im63wvaj7ajc2mzvy4uziq

Traces of ATCV-1 associated with laboratory component contamination

Kristín Rós Kjartansdóttir, Jens Friis-Nielsen, Maria Asplund, Sarah Mollerup, Tobias Mourier, Randi Holm Jensen, Thomas Arn Hansen, Alba Rey-Iglesia, Stine Raith Richter, David E. Alquezar-Planas, Pernille V. S. Olsen, Lasse Vinner (+7 others)
2015 Proceedings of the National Academy of Sciences of the United States of America  
doi:10.1073/pnas.1423756112 pmid:25654983 pmcid:PMC4352778 fatcat:rcc4szggkfhl3jg7zxqgfa3nty

Novel variation and de novo mutation rates in population-wide de novo assembled Danish trios

Søren Besenbacher, Siyang Liu, José M. G. Izarzugaza, Jakob Grove, Kirstine Belling, Jette Bork-Jensen, Shujia Huang, Thomas D. Als, Shengting Li, Rachita Yadav, Arcadio Rubio-García, Francesco Lescai (+35 others)
2015 Nature Communications  
C p G C − > A C p G C − > G C p G C − > T A − > C A − > G A − > T N o n C p G C − > A N o n C p G C − > G N o n C p G C − > T C p G C − > A C p G C − > G C p G C − > T A − > C A − > G A − > T N o n C p  ...  Using these sites only we can estimate: Similarly we can calculate: C HomRef i ðxÞ ¼ M HomRef dðc;xÞ M All dðc;xÞ ð4Þ Where i is either m or p and M All d ¼ variant-family pairs f 0 ; x 0 ð Þwhere all  ...  -G., R.G., P.V., S.Be. and S.R. Analysis of de novo mutations was performed by S.Be., J.G., F.L., P.V. and M.H.S.  ... 
doi:10.1038/ncomms6969 pmid:25597990 pmcid:PMC4309431 fatcat:fgpcwsc2hjgvfhjcznc54n7nme
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