| 1. |
- Sandve, Geir K., et al.
(författare)
-
The differential disease regulome
- 2011
-
Ingår i: BMC Genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 12
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Transcription factors in disease-relevant pathways represent potential drug targets, by impacting a distinct set of pathways that may be modulated through gene regulation. The influence of transcription factors is typically studied on a per disease basis, and no current resources provide a global overview of the relations between transcription factors and disease. Furthermore, existing pipelines for related large-scale analysis are tailored for particular sources of input data, and there is a need for generic methodology for integrating complementary sources of genomic information.Results: We here present a large-scale analysis of multiple diseases versus multiple transcription factors, with a global map of over-and under-representation of 446 transcription factors in 1010 diseases. This map, referred to as the differential disease regulome, provides a first global statistical overview of the complex interrelationships between diseases, genes and controlling elements. The map is visualized using the Google map engine, due to its very large size, and provides a range of detailed information in a dynamic presentation format.The analysis is achieved through a novel methodology that performs a pairwise, genome-wide comparison on the cartesian product of two distinct sets of annotation tracks, e.g. all combinations of one disease and one TF.The methodology was also used to extend with maps using alternative data sets related to transcription and disease, as well as data sets related to Gene Ontology classification and histone modifications. We provide a web-based interface that allows users to generate other custom maps, which could be based on precisely specified subsets of transcription factors and diseases, or, in general, on any categorical genome annotation tracks as they are improved or become available.Conclusion: We have created a first resource that provides a global overview of the complex relations between transcription factors and disease. As the accuracy of the disease regulome depends mainly on the quality of the input data, forthcoming ChIP-seq based binding data for many TFs will provide improved maps. We further believe our approach to genome analysis could allow an advance from the current typical situation of one-time integrative efforts to reproducible and upgradable integrative analysis. The differential disease regulome and its associated methodology is available at © 2011 Sandve et al; licensee BioMed Central Ltd.
|
|
| 2. |
- Sandve, Geir K., et al.
(författare)
-
The Genomic HyperBrowser: Inferential genomics at the sequence level
- 2010
-
Ingår i: Genome Biology. - : Springer Science and Business Media LLC. - 1474-7596 .- 1474-760X .- 1465-6906. ; 11
-
Tidskriftsartikel (refereegranskat)abstract
- The immense increase in the generation of genomic scale data poses an unmet analytical challenge, due to a lack of established methodology with the required flexibility and power. We propose a first principled approach to statistical analysis of sequence-level genomic information. We provide a growing collection of generic biological investigations that query pairwise relations between tracks, represented as mathematical objects, along the genome. The Genomic HyperBrowser implements the approach and is available at http://hyperbrowser.uio.no.© 2010 Sandve et al.; licensee BioMed Central Ltd.
|
|
| 3. |
- Basmo Ellingsen, Espen, et al.
(författare)
-
Telomerase as a Target for Therapeutic Cancer Vaccines and Considerations for Optimizing Their Clinical Potential
- 2021
-
Ingår i: Frontiers in Immunology. - : Frontiers Media S.A.. - 1664-3224. ; 12
-
Forskningsöversikt (refereegranskat)abstract
- Telomerase-based therapeutic cancer vaccines (TCVs) have been under clinical investigation for the past two decades. Despite past failures, TCVs have gained renewed enthusiasm for their potential to improve the efficacy of checkpoint inhibition. Telomerase stands as an attractive target for TCVs due to its almost universal presence in cancer and its essential function promoting tumor growth. Herein, we review tumor telomerase biology that may affect the efficacy of therapeutic vaccination and provide insights on optimal vaccine design and treatment combinations. Tumor types possessing mechanisms of increased telomerase expression combined with an immune permissive tumor microenvironment are expected to increase the therapeutic potential of telomerase-targeting cancer vaccines. Regardless, rational treatment combinations, such as checkpoint inhibitors, are likely necessary to bring out the true clinical potential of TCVs.
|
|
| 4. |
- Bjerner, Johan, et al.
(författare)
-
Non-parametric estimation of reference intervals in small non-Gaussian sample sets
- 2009
-
Ingår i: ACCREDITATION AND QUALITY ASSURANCE. - : Springer Science and Business Media LLC. - 0949-1775 .- 1432-0517. ; 14:4, s. 185-192
-
Tidskriftsartikel (refereegranskat)abstract
- This study aimed at validating common bootstrap algorithms for reference interval calculation.We simulated 1500 random sets of 50-120 results originating from eight different statistical distributions. In total, 97.5 percentile reference limits were estimated from bootstrapping 5000 replicates, with confidence limits obtained by: (a) normal, (b) from standard error, (c) bootstrap percentile (as in RefVal) (d) BCa, (e) basic, or (f) student methods. Reference interval estimates obtained with ordinary bootstrapping and confidence intervals by percentile method were accurate for distributions close to normality and devoid of outliers, but not for log-normal distributions with outliers. Outlier removal and transformation to normality improved reference interval estimation, and the basic method was superior in such cases. In conclusions, if the neighborhood of the relevant percentile contains non-normally distributed results, bootstrapping fails. The distribution of bootstrap estimates should be plotted, and a non-normal distribution should warrant transformation or outlier removal.
|
|
| 5. |
- Clancy, Trevor, et al.
(författare)
-
Immunological network signatures of cancer progression and survival.
- 2011
-
Ingår i: BMC medical genomics. - : Springer Science and Business Media LLC. - 1755-8794. ; 4:1
-
Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT: BACKGROUND: The immune contribution to cancer progression is complex and difficult to characterize. For example in tumors, immune gene expression is detected from the combination of normal, tumor and immune cells in the tumor microenvironment. Profiling the immune component of tumors may facilitate the characterization of the poorly understood roles immunity plays in cancer progression. However, the current approaches to analyze the immune component of a tumor rely on incomplete identification of immune factors. METHODS: To facilitate a more comprehensive approach, we created a ranked immunological relevance score for all human genes, developed using a novel strategy that combines text mining and information theory. We used this score to assign an immunological grade to gene expression profiles, and thereby quantify the immunological component of tumors. This immunological relevance score was benchmarked against existing manually curated immune resources as well as high-throughput studies. To further characterize immunological relevance for genes, the relevance score was charted against both the human interactome and cancer information, forming an expanded interactome landscape of tumor immunity. We applied this approach to expression profiles in melanomas, thus identifying and grading their immunological components, followed by identification of their associated protein interactions. RESULTS: The power of this strategy was demonstrated by the observation of early activation of the adaptive immune response and the diversity of the immune component during melanoma progression. Furthermore, the genome-wide immunological relevance score classified melanoma patient groups, whose immunological grade correlated with clinical features, such as immune phenotypes and survival. CONCLUSIONS: The assignment of a ranked immunological relevance score to all human genes extends the content of existing immune gene resources and enriches our understanding of immune involvement in complex biological networks. The application of this approach to tumor immunity represents an automated systems strategy that quantifies the immunological component in complex disease. In so doing, it stratifies patients according to their immune profiles, which may lead to effective computational prognostic and clinical guides.
|
|
| 6. |
- De Beule, Joachim, et al.
(författare)
-
Introducing Dynamics into the Field of Biosemiotics A Formal Account with Examples from Language and Immunology
- 2011
-
Ingår i: Biosemiotics. - : Springer Netherlands. - 1875-1342 .- 1875-1350. ; 4:1, s. 5-24
-
Tidskriftsartikel (refereegranskat)abstract
- Coding plays a universal and pervasive role in biological organization, in forms such as genetic coding (DNA to protein translation), RNA processing, gene regulation, protein modification, cell signalling, immune responses, epigenetic development and natural language. Nevertheless, the ways and means by which organic codes are formed and used are still poorly understood. A formal model is presented in this paper to investigate the emergence of conventional codes among code users. The relationship between the formation and the usage of codes is discussed, and a biological mechanism involving coding is identified in the context of the immune system.
|
|
| 7. |
- Ellingsen, Espen Basmo, et al.
(författare)
-
Characterization of the T cell receptor repertoire and melanoma tumor microenvironment upon combined treatment with ipilimumab and hTERT vaccination
- 2022
-
Ingår i: Journal of Translational Medicine. - : Springer Nature. - 1479-5876. ; 20
-
Tidskriftsartikel (refereegranskat)abstract
- Background: This clinical trial evaluated a novel telomerase-targeting therapeutic cancer vaccine, UV1, in combination with ipilimumab, in patients with metastatic melanoma. Translational research was conducted on patient-derived blood and tissue samples with the goal of elucidating the effects of treatment on the T cell receptor repertoire and tumor microenvironment.Methods: The trial was an open-label, single-center phase I/11a study. Eligible patients had unresectable metastatic melanoma. Patients received up to 9 UV1 vaccinations and four ipilimumab infusions. Clinical responses were assessed according to RECIST 1.1. Patients were followed up for progression-free survival (PFS) and overall survival (OS). Whole-exome and RNA sequencing, and multiplex immunofluorescence were performed on the biopsies. T cell receptor (TCR) sequencing was performed on the peripheral blood and tumor tissues.Results: Twelve patients were enrolled in the study. Vaccine-specific immune responses were detected in 91% of evaluable patients. Clinical responses were observed in four patients. The mPFS was 6.7 months, and the mOS was 66.3 months. There was no association between baseline tumor mutational burden, neoantigen load, IFN-gamma gene signature, tumor-infiltrating lymphocytes, and response to therapy. Tumor telomerase expression was confirmed in all available biopsies. Vaccine-enriched TCR clones were detected in blood and biopsy, and an increase in the tumor IFN-gamma gene signature was detected in clinically responding patients.Conclusion: Clinical responses were observed irrespective of established predictive biomarkers for checkpoint inhibitor efficacy, indicating an added benefit of the vaccine-induced T cells. The clinical and immunological read-out warrants further investigation of UV1 in combination with checkpoint inhibitors.
|
|
| 8. |
- Ellingsen, Espen Basmo, et al.
(författare)
-
Durable and dynamic hTERT immune responses following vaccination with the long-peptide cancer vaccine UV1 : long-term follow-up of three phase I clinical trials
- 2022
-
Ingår i: Journal for ImmunoTherapy of Cancer. - : BMJ Publishing Group Ltd. - 2051-1426. ; 10:5
-
Tidskriftsartikel (refereegranskat)abstract
- Background Therapeutic cancer vaccines represent a promising approach to improve clinical outcomes with immune checkpoint inhibition. UV1 is a second generation telomerase-targeting therapeutic cancer vaccine being investigated across multiple indications. Although telomerase is a near-universal tumor target, different treatment combinations applied across indications may affect the induced immune response. Three phase I/IIa clinical trials covering malignant melanoma, non-small cell lung cancer, and prostate cancer have been completed, with patients in follow-up for up to 8 years.Methods 52 patients were enrolled across the three trials. UV1 was given as monotherapy in the lung cancer trial and concurrent with combined androgen blockade in the prostate cancer trial. In the melanoma study, patients initiated ipilimumab treatment 1 week after the first vaccine dose. Patients were followed for UV1-specific immune responses at frequent intervals during vaccination, and every 6 months for up to 8 years in a follow-up period. Phenotypic and functional characterizations were performed on patient-derived vaccine-specific T cell responses.Results In total, 78.4% of treated patients mounted a measurable vaccine-induced T cell response in blood. The immune responses in the malignant melanoma trial, where UV1 was combined with ipilimumab, occurred more rapidly and frequently than in the lung and prostate cancer trials. In several patients, immune responses peaked years after their last vaccination. An in-depth characterization of the immune responses revealed polyfunctional CD4+ T cells producing interferon-gamma and tumor necrosis factor-alpha on interaction with their antigen.Conclusion Long-term immunomonitoring of patients showed highly dynamic and persistent telomerase peptide-specific immune responses lasting up to 7.5 years after the initial vaccination, suggesting a plausible functional role of these T cells in long-term survivors. The superior immune response kinetics observed in the melanoma study substantiate the rationale for future combinatorial treatment strategies with UV1 vaccination and checkpoint inhibition for rapid and frequent induction of anti-telomerase immune responses in patients with cancer.
|
|
| 9. |
- Fromm, Bastian, et al.
(författare)
-
MirGeneDB 2.0 : the metazoan microRNA complement
- 2020
-
Ingår i: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 48:D1, s. D132-D141
-
Tidskriftsartikel (refereegranskat)abstract
- Small non-coding RNAs have gained substantial attention due to their roles in animal development and human disorders. Among them, microRNAs are special because individual gene sequences are conserved across the animal kingdom. In addition, unique and mechanistically well understood features can clearly distinguish bona fide miRNAs from the myriad other small RNAs generated by cells. However, making this distinction is not a common practice and, thus, not surprisingly, the heterogeneous quality of available miRNA complements has become a major concern in microRNA research. We addressed this by extensively expanding our curated microRNA gene database - MirGeneDB - to 45 organisms, encompassing a wide phylogenetic swath of animal evolution. By consistently annotating and naming 10,899 microRNA genes in these organisms, we show that previous microRNA annotations contained not only many false positives, but surprisingly lacked >2000 bona fide microRNAs. Indeed, curated microRNA complements of closely related organisms are very similar and can be used to reconstruct ancestral miRNA repertoires. MirGeneDB represents a robust platform for microRNA-based research, providing deeper and more significant insights into the biology and evolution of miRNAs as well as biomedical and biomarker research.
|
|
| 10. |
- Gopalakrishnan, Shyam, et al.
(författare)
-
The population genomic legacy of the second plague pandemic
- 2022
-
Ingår i: Current Biology. - : Elsevier. - 0960-9822 .- 1879-0445. ; 32:21, s. 4743-4751.e6
-
Tidskriftsartikel (refereegranskat)abstract
- Human populations have been shaped by catastrophes that may have left long-lasting signatures in their genomes. One notable example is the second plague pandemic that entered Europe in ca. 1,347 CE and repeatedly returned for over 300 years, with typical village and town mortality estimated at 10%–40%.1 It is assumed that this high mortality affected the gene pools of these populations. First, local population crashes reduced genetic diversity. Second, a change in frequency is expected for sequence variants that may have affected survival or susceptibility to the etiologic agent (Yersinia pestis).2 Third, mass mortality might alter the local gene pools through its impact on subsequent migration patterns. We explored these factors using the Norwegian city of Trondheim as a model, by sequencing 54 genomes spanning three time periods: (1) prior to the plague striking Trondheim in 1,349 CE, (2) the 17th–19th century, and (3) the present. We find that the pandemic period shaped the gene pool by reducing long distance immigration, in particular from the British Isles, and inducing a bottleneck that reduced genetic diversity. Although we also observe an excess of large FST values at multiple loci in the genome, these are shaped by reference biases introduced by mapping our relatively low genome coverage degraded DNA to the reference genome. This implies that attempts to detect selection using ancient DNA (aDNA) datasets that vary by read length and depth of sequencing coverage may be particularly challenging until methods have been developed to account for the impact of differential reference bias on test statistics.
|
|
| 11. |
- Høye, Eirik, et al.
(författare)
-
A comprehensive framework for analysis of microRNA sequencing data in metastatic colorectal cancer
- 2022
-
Ingår i: NAR Cancer. - : Oxford University Press (OUP). - 2632-8674. ; 4:1
-
Tidskriftsartikel (refereegranskat)abstract
- Although microRNAs (miRNAs) contribute to all hallmarks of cancer, miRNA dysregulation in metastasis remains poorly understood. The aim of this work was to reliably identify miRNAs associated with metastatic progression of colorectal cancer (CRC) using novel and previously published next-generation sequencing (NGS) datasets generated from 268 samples of primary (pCRC) and metastatic CRC (mCRC; liver, lung and peritoneal metastases) and tumor adjacent tissues. Differential expression analysis was performed using a meticulous bioinformatics pipeline, including only bona fide miRNAs, and utilizing miRNA-tailored quality control and processing. Five miRNAs were identified as up-regulated at multiple metastatic sites Mir-210_3p, Mir-191_5p, Mir-8-P1b_3p [mir-141–3p], Mir-1307_5p and Mir-155_5p. Several have previously been implicated in metastasis through involvement in epithelial-to-mesenchymal transition and hypoxia, while other identified miRNAs represent novel findings. The use of a publicly available pipeline facilitates reproducibility and allows new datasets to be added as they become available. The set of miRNAs identified here provides a reliable starting-point for further research into the role of miRNAs in metastatic progression.
|
|
| 12. |
- Kresse, Stine H., et al.
(författare)
-
Integrative Analysis Reveals Relationships of Genetic and Epigenetic Alterations in Osteosarcoma
- 2012
-
Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Osteosarcomas are the most common non-haematological primary malignant tumours of bone, and all conventional osteosarcomas are high-grade tumours showing complex genomic aberrations. We have integrated genome-wide genetic and epigenetic profiles from the EuroBoNeT panel of 19 human osteosarcoma cell lines based on microarray technologies. Principal Findings: The cell lines showed complex patterns of DNA copy number changes, where genomic copy number gains were significantly associated with gene-rich regions and losses with gene-poor regions. By integrating the datasets, 350 genes were identified as having two types of aberrations (gain/over-expression, hypo-methylation/over-expression, loss/under-expression or hyper-methylation/under-expression) using a recurrence threshold of 6/19 (>30%) cell lines. The genes showed in general alterations in either DNA copy number or DNA methylation, both within individual samples and across the sample panel. These 350 genes are involved in embryonic skeletal system development and morphogenesis, as well as remodelling of extracellular matrix. The aberrations of three selected genes, CXCL5, DLX5 and RUNX2, were validated in five cell lines and five tumour samples using PCR techniques. Several genes were hyper-methylated and under-expressed compared to normal osteoblasts, and expression could be reactivated by demethylation using 5-Aza-2′-deoxycytidine treatment for four genes tested; AKAP12, CXCL5, EFEMP1 and IL11RA. Globally, there was as expected a significant positive association between gain and over-expression, loss and under-expression as well as hyper-methylation and under-expression, but gain was also associated with hyper-methylation and under-expression, suggesting that hyper-methylation may oppose the effects of increased copy number for detrimental genes. Conclusions: Integrative analysis of genome-wide genetic and epigenetic alterations identified dependencies and relationships between DNA copy number, DNA methylation and mRNA expression in osteosarcomas, contributing to better understanding of osteosarcoma biology. © 2012 Kresse et al.
|
|
| 13. |
- Lindberg, Johan, 1977-
(författare)
-
Transcriptional patterns in inflammatory disease
- 2008
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In the studies this thesis is based upon, microarrays were applied to profilemRNA populations in biological samples to gain insights into transcriptionalpatterns and their relation to inflammatory disease.Rheumatoid arthritis (RA) is a chronic inflammatory disease, which leads todegradation of cartilage and bone. RA is characterized by synovial inflammationwith varying levels of tissue heterogeneity. This was confirmed by microarrayanalyses of multiple biopsies from the joints of 13 patients, which showed interindividualvariation in transcript populations to be higher than intra‐individualvariationTherapeutic antibodies targeting TNF‐α have revolutionized treatment of RA,although some patients do not respond well. Identification of non‐responders isimportant, not only because anti‐TNF treatment elevates the risk of infections,but also because of the cost of treatment. A proof‐of‐concept study to investigatetranscriptional effects of anti‐TNF treatment demonstrated that differencesbetween response groups could be identified and that these differences revealedbiological themes related to inflammatory disease.A subsequent study was therefore initiated with a larger cohort of 62 patients toinvestigate gene expression patterns in the synovium prior to anti‐TNFtreatment. Here, the heterogeneity was even more pronounced, thetranscriptional patterns were confounded by the presence of synovial aggregatesand only a weak therapy‐correlated signature was detected. The presence oflymphocyte aggregates was found to correlate to response to therapy, which isconsistent with previous findings indicating a higher level of inflammation ingood responding patients.Periodontitis is an inflammatory disease with many similarities to RA. Both areincurable chronic auto‐immune diseases, characterized by tissue destructionwith common genetic associations. Individuals with RA are at higher risk ofaccumulating significant periodontal problems than the general population. PGE2(prostaglandin E2) is known to stimulate inflammation and bone resorption inperiodontitis. In further studies, microarrays were applied in a time seriesdesign on human gingival fibroblats to explore the signal transduction pathwayscontrolling TNF‐α induced PGE2 synthesis in order to identify novel therapeutictargets. The JNK and NF‐kb pathways were identified as being differentiallyaffected by TNF‐a treatment. The transcriptional patterns were further verifiedusing antibodies against phosphorylated JNK/NF‐kb molecules and specificinhibitors of the JNK and NF‐kb signaling cascades.
|
|
| 14. |
- Mattingsdal, Morten, et al.
(författare)
-
Pathway analysis of genetic markers associated with a functional MRI faces paradigm implicates polymorphisms in calcium responsive pathways
- 2013
-
Ingår i: NeuroImage. - 1053-8119 .- 1095-9572. ; 70, s. 143-149
-
Tidskriftsartikel (refereegranskat)abstract
- Several lines of evidence suggest that common polygenic variation influences brain function in humans. Combining high-density genetic markers with brain imaging techniques is constricted by the practicalities of collecting sufficiently large brain imaging samples. Pathway analysis promises to leverage knowledge on function of genes to detect recurring signals of moderate effect. We adapt this approach, exploiting the deep information collected on brain function by fMRI methods, to identify molecular pathways containing genetic variants which influence brain activation during a commonly applied experiment based on a face matching task (n=246) which was developed to study neural processing of faces displaying negative emotions. Genetic markers moderately associated (p<10(-4)) with whole brain activation phenotypes constructed by applying principal components to contrast maps, were tested for pathway enrichment using permutation based methods. The most significant pathways are related to post NMDA receptor activation events, driven by genetic variants in calcium/calmodulin-dependent protein kinase II (CAMK2G, CAMK2D) and a calcium-regulated nucleotide exchange factor (RASGRF2) in which all are activated by intracellular calcium/calmodulin. The most significant effect of the combined polygenic model were localized to the left inferior frontal gyrus (p=1.03 × 10(-9)), a region primarily involved in semantic processing but also involved in processing negative emotions. These findings suggest that pathway analysis of GWAS results derived from principal component analysis of fMRI data is a promising method, to our knowledge, not previously described.
|
|
| 15. |
- Njølstad, Pål Rasmus, et al.
(författare)
-
Roadmap for a precision-medicine initiative in the Nordic region
- 2019
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718.
-
Tidskriftsartikel (refereegranskat)abstract
- The Nordic region, comprising primarily Denmark, Estonia, Finland, Iceland, Norway and Sweden, has many of the necessary characteristics for being at the forefront of genome-based precision medicine. These include egalitarian and universal healthcare, expertly curated patient and population registries, biobanks, large population-based prospective cohorts linked to registries and biobanks, and a widely embraced sense of social responsibility that motivates public engagement in biomedical research. However, genome-based precision medicine can be achieved only through coordinated action involving all actors in the healthcare sector. Now is an opportune time to organize scientists in the Nordic region, together with other stakeholders including patient representatives, governments, pharmaceutical companies, academic institutions and funding agencies, to initiate a Nordic Precision Medicine Initiative. We present a roadmap for how this organization can be created. The Initiative should facilitate research, clinical trials and knowledge transfer to meet regional and global health challenges.
|
|
| 16. |
- Olafsdottir, Elinborg J., et al.
(författare)
-
Breast cancer survival in Nordic BRCA2 mutation carriers—unconventional association with oestrogen receptor status
- 2020
-
Ingår i: British Journal of Cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 123:11, s. 1608-1615
-
Tidskriftsartikel (refereegranskat)abstract
- Background: The natural history of breast cancer among BRCA2 carriers has not been clearly established. In a previous study from Iceland, positive ER status was a negative prognostic factor. We sought to identify factors that predicted survival after invasive breast cancer in an expanded cohort of BRCA2 carriers. Methods: We studied 608 women with invasive breast cancer and a pathogenic BRCA2 mutation (variant) from four Nordic countries. Information on prognostic factors and treatment was retrieved from health records and by analysis of archived tissue specimens. Hazard ratios (HR) were estimated for breast cancer-specific survival using Cox regression. Results: About 77% of cancers were ER-positive, with the highest proportion (83%) in patients under 40 years. ER-positive breast cancers were more likely to be node-positive (59%) than ER-negative cancers (34%) (P < 0.001). The survival analysis included 584 patients. Positive ER status was protective in the first 5 years from diagnosis (multivariate HR = 0.49; 95% CI 0.26–0.93, P = 0.03); thereafter, the effect was adverse (HR = 1.91; 95% CI 1.07–3.39, P = 0.03). The adverse effect of positive ER status was limited to women who did not undergo endocrine treatment (HR = 2.36; 95% CI 1.26–4.44, P = 0.01) and patients with intact ovaries (HR = 1.99; 95% CI 1.11–3.59, P = 0.02). Conclusions: The adverse effect of a positive ER status in BRCA2 carriers with breast cancer may be contingent on exposure to ovarian hormones.
|
|
| 17. |
- Pedicini, Marco, et al.
(författare)
-
Combining network modeling and gene expression microarray analysis to explore the dynamics of Th1 and Th2 cell regulation.
- 2010
-
Ingår i: PLoS computational biology. - : Public Library of Science (PLoS). - 1553-7358 .- 1553-734X. ; 6:12
-
Tidskriftsartikel (refereegranskat)abstract
- Two T helper (Th) cell subsets, namely Th1 and Th2 cells, play an important role in inflammatory diseases. The two subsets are thought to counter-regulate each other, and alterations in their balance result in different diseases. This paradigm has been challenged by recent clinical and experimental data. Because of the large number of genes involved in regulating Th1 and Th2 cells, assessment of this paradigm by modeling or experiments is difficult. Novel algorithms based on formal methods now permit the analysis of large gene regulatory networks. By combining these algorithms with in silico knockouts and gene expression microarray data from human T cells, we examined if the results were compatible with a counter-regulatory role of Th1 and Th2 cells. We constructed a directed network model of genes regulating Th1 and Th2 cells through text mining and manual curation. We identified four attractors in the network, three of which included genes that corresponded to Th0, Th1 and Th2 cells. The fourth attractor contained a mixture of Th1 and Th2 genes. We found that neither in silico knockouts of the Th1 and Th2 attractor genes nor gene expression microarray data from patients with immunological disorders and healthy subjects supported a counter-regulatory role of Th1 and Th2 cells. By combining network modeling with transcriptomic data analysis and in silico knockouts, we have devised a practical way to help unravel complex regulatory network topology and to increase our understanding of how network actions may differ in health and disease.
|
|
| 18. |
- Rodríguez-Varela, Ricardo, et al.
(författare)
-
The genetic history of Scandinavia from the Roman Iron Age to the present
- 2023
-
Ingår i: Cell. - : Elsevier. - 0092-8674 .- 1097-4172. ; 186:1, s. 32-46
-
Tidskriftsartikel (refereegranskat)abstract
- We investigate a 2,000-year genetic transect through Scandinavia spanning the Iron Age to the present, based on 48 new and 249 published ancient genomes and genotypes from 16,638 modern individuals. We find regional variation in the timing and magnitude of gene flow from three sources: the eastern Baltic, the British-Irish Isles, and southern Europe. British-Irish ancestry was widespread in Scandinavia from the Viking period, whereas eastern Baltic ancestry is more localized to Gotland and central Sweden. In some regions, a drop in current levels of external ancestry suggests that ancient immigrants contributed proportionately less to the modern Scandinavian gene pool than indicated by the ancestry of genomes from the Viking and Medieval periods. Finally, we show that a north-south genetic cline that characterizes modern Scandinavians is mainly due to the differential levels of Uralic ancestry and that this cline existed in the Viking Age and possibly earlier.
|
|
| 19. |
- Shungin, Dmitry, 1982-
(författare)
-
Interplay between genetics and environment in obesity
- 2015
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background. Being one of the largest current global health problems, obesity is a result of interplay between genetic and environmental factors. In this thesis we studied the genetic underpinning of adipose tissue distribution; investigated causality between obesity and periodontitis using instrumental variable analyses in genetic epidemiology settings; studied interactions between obesity-associated loci and physical activity on obesity; and checked if loci identified in genome-wide association studies are good candidates for gene-environment interactions using heterogeneity of variance analyses.Methods. In Paper 1 we performed a meta-analysis of large-scale genetic association studies for waist traits in 224,459 participants followed by a variety of statistical and bioinformatics methods to obtain insights into the biology of the underlying adipose distributions. In Paper 2 we used genetic variants associated with body mass index (BMI) as instruments within a Mendelian randomization framework to study causality between obesity and periodontitis in 49,066 participants. In Paper 3 we studied the interaction between an FTO single nucleotide polymorphism (SNP) rs9939609 and physical activity in obesity outcomes through meta-analysis of 237,434 participants. In Paper 4 we evaluated if SNPs established through main-effects meta-analysis of genome-wide association studies represent strong or weak candidates for gene-environment interactions, inferred by the degree of phenotypic heterogeneity across genotypes at a given SNP locus.Results. In Paper 1 we identified 49 loci (33 novel) associated with waist-to-hip ratio adjusted for BMI (P<5×10-8), 20 of which displayed significant sexual dimorphism, of which 19 displayed a stronger effect in women than in men. We also detected 19 additional loci newly associated with related waist and hip circumference measures. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation, and insulin resistance as processes affecting fat distribution, providing insights into potential pathophysiological mechanisms. In Paper 2 we confirmed observational associations between BMI and periodontitis with a pooled odds ratio (OR) of 1.13 per standard deviation increase in BMI (95%CI:1.03, 1.24) in all participants and 1.25 (95%CI:1.10, 1.42) in participants with clinical data. The instrumental variable meta-analysis yielded an OR of 1.05 (95%CI:0.80, 1.38) per BMI standard deviation, and 0.90 (95%CI:0.56, 1.46) in participants with clinical data. In Paper 3 we showed that physical activity attenuates the influence of FTO variation in rs9939609 on obesity (Pinteraction=0.001) with the A allele of rs9939609 increasing the odds of obesity less in the physically active group, with a per-allele OR of 1.22 (95%CI:1.19, 1.25), than in the inactive group, with a per-allele OR of 1.30 (95%CI:1.24, 1.36). In Paper 4 we show that rank-ordered distributions of P-values between marginal effects genome-wide association studies (GWAS) and heterogeneity of variance analyses for all SNPs for BMI and lipid traits have very weak correlations for most traits (Spearman rho of 0.0034 for total cholesterol and 0.0044 for BMI for the squared phenotype residuals regression method) indicating that variants with strong marginal effects are in general poor candidates for gene-environment interactions based on heterogeneity of variance analyses, although a small number of variants convey strong marginal and variance effects, such as those at the FTO locus, meaning that they are likely to convey both marginal and interaction effects.Conclusion. The work outlined in this thesis sheds light on the complexity of genetic and environmental factors in obesity. We have identified novel loci associated with waist traits and described pathways implicated in adipose distribution. We have shown that based on Mendelian randomization analyses the association between periodontitis and obesity is unlikely to be causal. We have confirmed interactions between a bona-fide obesity locus (FTO) and physical activity on obesity and have shown that, in contrast to FTO, the majority of genetic variants identified through GWAS are unlikely to be good candidates for gene-environment interactions based on heterogeneity of variance analyses.
|
|
| 20. |
- Späth, Florentin, et al.
(författare)
-
Pre-diagnostic serum levels of EGFR and ErbB2 and genetic glioma risk variants : a nested case-control study
- 2016
-
Ingår i: Tumor Biology. - : Springer Science and Business Media LLC. - 1010-4283 .- 1423-0380. ; 37:8, s. 11065-11072
-
Tidskriftsartikel (refereegranskat)abstract
- Genetic variants have been associated with the risk of developing glioma, but functional mechanisms on disease phenotypic traits remain to be investigated. One phenotypic trait of glioblastoma is the mutation and amplification of the epidermal growth factor receptor (EGFR) gene. We investigated associations between pre-diagnostic serum protein concentrations of EGFR and ErbB2, both members of the EGFR family, and future risk of glioma. Further, we studied if EGFR glioma risk variants were associated with EGFR and ErbB2 serum levels. We assessed the associations between genetic glioma risk variants and serum concentrations of EGFR and ErbB2, as measured in pre-diagnostic cohort serum samples of 593 glioma patients and 590 matched cancer-free controls. High serum EGFR and ErbB2 levels were associated with risk of developing glioblastoma (P = 0.008; OR = 1.58, 95 % CI = 1.13-2.22 and P = 0.017, OR = 1.63, 95 % CI = 1.09-2.44, respectively). High serum ErbB2 concentration was also associated with glioma risk overall (P = 0.049; OR = 1.39, 95 % CI = 1.00-1.93). Glioma risk variants were not associated with high serum protein abundance. In contrast, the EGFR risk variant rs4947986 (T) was correlated with decreased EGFR serum levels (study cohort P = 0.024 and controls P = 0.009). To our knowledge, this is the first study showing an association of EGFR and ErbB2 serum levels with glioma more than a decade before diagnosis, indicating that EGFR and ErbB2 serum proteins are important in early gliomagenesis. However, we did not find evidence that glioma risk variants were associated with high pre-diagnostic serum concentrations of EGFR and ErbB2.
|
|
| 21. |
- Wibom, Carl, et al.
(författare)
-
Investigation of Established Genetic Risk Variants for Glioma in Prediagnostic Samples from a Population-Based Nested Case-Control Study
- 2015
-
Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - 1055-9965 .- 1538-7755. ; 24:5, s. 810-816
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Although glioma etiology is poorly understood in general, growing evidence indicates a genetic component. Four large genome-wide association studies (GWAS) have linked common genetic variants with an increased glioma risk. However, to date, these studies are based largely on a case-control design, where cases have been recruited at the time of or after diagnosis. They may therefore suffer from a degree of survival bias, introduced when rapidly fatal cases are not included.Methods: To confirm glioma risk variants in a prospective setting, we have analyzed 11 previously identified risk variants in a set of prediagnostic serum samples with 598 cases and 595 matched controls. Serum samples were acquired from The Janus Serum Bank, a Norwegian population-based biobank reserved for cancer research.Results: We confirmed the association with glioma risk for variants within five genomic regions: 8q24.21 (CCDC26), 9p21.3 (CDKN2B-AS1), 11q23.3 (PHLDB1), 17p13.1 (TP53), and 20q13.33 (RTEL1). However, previously identified risk variants within the 7p11.2 (EGFR) region were not confirmed by this study.Conclusions: Our results indicate that the risk variants that were confirmed by this study are truly associated with glioma risk and may, consequently, affect gliomagenesis. Though the lack of positive confirmation of EGFR risk variants may be attributable to relatively limited statistical power, it nevertheless raises the question whether they truly are risk variants or markers for glioma prognosis.Impact: Our findings indicate the need for further studies to clarify the role of glioma risk loci with respect to prolonged survival versus etiology.
|
|
