| 1. |
- Wang, Zhaoming, et al.
(författare)
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Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33
- 2014
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:24, s. 6616-6633
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10(-39); Region 3: rs2853677, P = 3.30 × 10(-36) and PConditional = 2.36 × 10(-8); Region 4: rs2736098, P = 3.87 × 10(-12) and PConditional = 5.19 × 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10(-6); and Region 6: rs10069690, P = 7.49 × 10(-15) and PConditional = 5.35 × 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10(-18) and PConditional = 7.06 × 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.
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| 2. |
- Glimelius, Bengt, et al.
(författare)
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U-CAN : a prospective longitudinal collection of biomaterials and clinical information from adult cancer patients in Sweden.
- 2018
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Ingår i: Acta Oncologica. - : Taylor & Francis. - 0284-186X .- 1651-226X. ; 57:2, s. 187-194
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Tidskriftsartikel (refereegranskat)abstract
- Background: Progress in cancer biomarker discovery is dependent on access to high-quality biological materials and high-resolution clinical data from the same cases. To overcome current limitations, a systematic prospective longitudinal sampling of multidisciplinary clinical data, blood and tissue from cancer patients was therefore initiated in 2010 by Uppsala and Umeå Universities and involving their corresponding University Hospitals, which are referral centers for one third of the Swedish population.Material and Methods: Patients with cancer of selected types who are treated at one of the participating hospitals are eligible for inclusion. The healthcare-integrated sampling scheme encompasses clinical data, questionnaires, blood, fresh frozen and formalin-fixed paraffin-embedded tissue specimens, diagnostic slides and radiology bioimaging data.Results: In this ongoing effort, 12,265 patients with brain tumors, breast cancers, colorectal cancers, gynecological cancers, hematological malignancies, lung cancers, neuroendocrine tumors or prostate cancers have been included until the end of 2016. From the 6914 patients included during the first five years, 98% were sampled for blood at diagnosis, 83% had paraffin-embedded and 58% had fresh frozen tissues collected. For Uppsala County, 55% of all cancer patients were included in the cohort.Conclusions: Close collaboration between participating hospitals and universities enabled prospective, longitudinal biobanking of blood and tissues and collection of multidisciplinary clinical data from cancer patients in the U-CAN cohort. Here, we summarize the first five years of operations, present U-CAN as a highly valuable cohort that will contribute to enhanced cancer research and describe the procedures to access samples and data.
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| 3. |
- Sampson, Joshua N., et al.
(författare)
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Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for 13 Cancer Types
- 2015
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 107:12
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Tidskriftsartikel (refereegranskat)abstract
- Background: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites. Methods: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers. Results: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, h(l)(2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (rho = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (rho = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (rho = 0.51, SE = 0.18), and bladder and lung (rho = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures. Conclusion: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.
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| 4. |
- Chotiwan, Nunya, et al.
(författare)
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Type I interferon shapes brain distribution and tropism of tick-borne flavivirus
- 2023
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Viral tropism within the brain and the role(s) of vertebrate immune response to neurotropic flaviviruses infection is largely understudied. We combine multimodal imaging (cm-nm scale) with single nuclei RNA-sequencing to study Langat virus in wildtype and interferon alpha/beta receptor knockout (Ifnar-/-) mice to visualize viral pathogenesis and define molecular mechanisms. Whole brain viral infection is imaged by Optical Projection Tomography coregistered to ex vivo MRI. Infection is limited to grey matter of sensory systems in wildtype mice, but extends into white matter, meninges and choroid plexus in Ifnar-/- mice. Cells in wildtype display strong type I and II IFN responses, likely due to Ifnb expressing astrocytes, infiltration of macrophages and Ifng-expressing CD8+ NK cells, whereas in Ifnar-/-, the absence of this response contributes to a shift in cellular tropism towards non-activated resident microglia. Multimodal imaging-transcriptomics exemplifies a powerful way to characterize mechanisms of viral pathogenesis and tropism.
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| 5. |
- Odaga, John, et al.
(författare)
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Empowering districts to target priorities for improving child health service in Uganda using change management and rapid assessment methods
- 2016
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Ingår i: Global Health Action. - : Informa UK Limited. - 1654-9716 .- 1654-9880. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Background: Local health system managers in low- and middle-income countries have the responsibility to set health priorities and allocate resources accordingly. Although tools exist to aid this process, they are not widely applied for various reasons including non-availability, poor knowledge of the tools, and poor adaptability into the local context. In Uganda, delivery of basic services is devolved to the District Local Governments through the District Health Teams (DHTs). The Community and District Empowerment for Scale-up (CODES) project aims to provide a set of management tools that aid contextualised priority setting, fund allocation, and problem-solving in a systematic way to improve effective coverage and quality of child survival interventions. Design: Although the various tools have previously been used at the national level, the project aims to combine them in an integral way for implementation at the district level. These tools include Lot Quality Assurance Sampling (LQAS) surveys to generate local evidence, Bottleneck analysis and Causal analysis as analytical tools, Continuous Quality Improvement, and Community Dialogues based on Citizen Report Cards and U reports. The tools enable identification of gaps, prioritisation of possible solutions, and allocation of resources accordingly. This paper presents some of the tools used by the project in five districts in Uganda during the proof-of-concept phase of the project. Results: All five districts were trained and participated in LQAS surveys and readily adopted the tools for priority setting and resource allocation. All districts developed health operational work plans, which were based on the evidence and each of the districts implemented more than three of the priority activities which were included in their work plans. Conclusions: In the five districts, the CODES project demonstrated that DHTs can adopt and integrate these tools in the planning process by systematically identifying gaps and setting priority interventions for child survival.
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| 6. |
- Rajaraman, Preetha, et al.
(författare)
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Genome-wide association study of glioma and meta-analysis
- 2012
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Ingår i: Human Genetics. - : SPRINGER. - 0340-6717 .- 1432-1203. ; 131:12, s. 1877-1888
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Tidskriftsartikel (refereegranskat)abstract
- Gliomas account for approximately 80 % of all primary malignant brain tumors and, despite improvements in clinical care over the last 20 years, remain among the most lethal tumors, underscoring the need for gaining new insights that could translate into clinical advances. Recent genome-wide association studies (GWAS) have identified seven new susceptibility regions. We conducted a new independent GWAS of glioma using 1,856 cases and 4,955 controls (from 14 cohort studies, 3 case-control studies, and 1 population-based case-only study) and found evidence of strong replication for three of the seven previously reported associations at 20q13.33 (RTEL), 5p15.33 (TERT), and 9p21.3 (CDKN2BAS), and consistent association signals for the remaining four at 7p11.2 (EGFR both loci), 8q24.21 (CCDC26) and 11q23.3 (PHLDB1). The direction and magnitude of the signal were consistent for samples from cohort and case-control studies, but the strength of the association was more pronounced for loci rs6010620 (20q,13.33; RTEL) and rs2736100 (5p15.33, TERT) in cohort studies despite the smaller number of cases in this group, likely due to relatively more higher grade tumors being captured in the cohort studies. We further examined the 85 most promising single nucleotide polymorphism (SNP) markers identified in our study in three replication sets (5,015 cases and 11,601 controls), but no new markers reached genome-wide significance. Our findings suggest that larger studies focusing on novel approaches as well as specific tumor subtypes or subgroups will be required to identify additional common susceptibility loci for glioma risk.
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| 7. |
- Rosendal, Ebba, 1993-, et al.
(författare)
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Transcriptional response to tick-borne flavivirus infection in neurons, astrocytes and microglia in vivo and in vitro
- 2024
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Ingår i: Viruses. - : MDPI. - 1999-4915. ; 16:8
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Tidskriftsartikel (refereegranskat)abstract
- Tick-borne encephalitis virus (TBEV) is a neurotropic member of the genus Orthoflavivirus (former Flavivirus) and is of significant health concern in Europe and Asia. TBEV pathogenesis may occur directly via virus-induced damage to neurons or through immunopathology due to excessive inflammation. While primary cells isolated from the host can be used to study the immune response to TBEV, it is still unclear how well these reflect the immune response elicited in vivo. Here, we compared the transcriptional response to TBEV and the less pathogenic tick-borne flavivirus, Langat virus (LGTV), in primary monocultures of neurons, astrocytes and microglia in vitro, with the transcriptional response in vivo captured by single-nuclei RNA sequencing (snRNA-seq) of a whole mouse cortex. We detected similar transcriptional changes induced by both LGTV and TBEV infection in vitro, with the lower response to LGTV likely resulting from slower viral kinetics. Gene set enrichment analysis showed a stronger transcriptional response in vivo than in vitro for astrocytes and microglia, with a limited overlap mainly dominated by interferon signaling. Together, this adds to our understanding of neurotropic flavivirus pathogenesis and the strengths and limitations of available model systems.
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| 8. |
- Öhlén, Joakim, 1958, et al.
(författare)
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Symptom alleviation profiles during the last week of life. A register based quality of end-of-life study
- 2015
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Ingår i: International Society for Quality of Life Research 22nd Annual Conference. October 21-24, Vancouver, Canada.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Aims: To examine symptom alleviation profiles as quality indicators that reflect care and wellbeing of patients during the last week of life and improve understanding of patterns. Methods: A cross-sectional design was chosen using data from the Swedish Palliative Care Registry, a national register for all deaths that contains professionals’ retrospectively-reported data about quality indicators reflecting care and wellbeing of patients during the last week of life. All deceased adults (>18 years) with expected deaths, registered in the register in 2012 and 2013 (approximately 60% of the total death population in Sweden each year) were included. Descriptive statistical analysis of the sample and a preliminary latent class analysis have been performed to identify symptom alleviation profiles, including alleviation of pain, nausea, anxiety, shortness of breath, confusion, and breathing rattles. Analyses of demographic and health-related characteristics predictive of latent class membership are ongoing. Results: 38766 men and 49117 women were included. 65% were 18-59 years of age, 19.0% were 60-79 years of age, and 16.0% were 80-110 years of age. Neoplasms (36.7%), cardiovascular diseases (31.1 %) and dementia (12.4%) were the most common underlying causes of death. Nursing home (39,7%), hospital wards (27,7%), hospice and specialised palliative care in-patient units (11,5%), municipality short-term facilities (8,8%) and specialised palliative home care (6,8%) were the most common locations of care. The most frequent symptoms were pain (70.9%), breathing rattles (52.4%), anxiety (46.1%), confusion (29.0%), and shortness of breath (25.2%). Total symptom relief was reported for 52.4% of patients experiencing pain, 23.7% of those experiencing breathing rattles, 8.5% of those experiencing anxiety, 5.1% experiencing confusion and 9.0% experiencing breathlessness. Preliminary results suggest 5 latent classes that represent unique symptom alleviation profiles, with class sizes ranging from 9% to 33%. Conclusion: Symptom alleviation is a quality indicator for palliative care that is of significant importance to the wellbeing of people during their last week of life. A better understanding of profiles and predictors of symptom alleviation can inform the development of care quality for the purpose of enhanced quality of end-of-life across different diagnoses and locations of care.
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| 9. |
- Bethke, Lara, et al.
(författare)
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CASP8 D302H and meningioma risk : an analysis of five case-control series
- 2009
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Ingår i: Cancer Letters. - Clare : Elsevier. - 0304-3835 .- 1872-7980. ; 273:2, s. 312-315
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Tidskriftsartikel (refereegranskat)abstract
- Caspase 8 (CASP8) is a key regulator of apoptosis or programmed cell death, and hence a defence against cancer. The CASP8 polymorphism D302H has recently been shown to influence the risk of breast cancer. We tested the hypothesis that the CASP8 polymorphism D302H may influence risk of meningioma through analysis of five independent series of case patients and controls (n=631 and 637, respectively). Carrier status for 302H was not associated with a statistically significantly increased risk (OR=1.16; 95% CI: 0.87-1.53; P=0.31) making it unlikely that this variant contributes to the inherited risk of meningioma.
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| 10. |
- Bethke, Lara, et al.
(författare)
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Comprehensive analysis of DNA repair gene variants and risk of meningioma
- 2008
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press. - 0027-8874 .- 1460-2105. ; 100:4, s. 270-276
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Tidskriftsartikel (refereegranskat)abstract
- Background: Meningiomas account for up to 37% of all primary brain tumors. Genetic susceptibility to meningioma is well established, with the risk among relatives of meningioma patients being approximately threefold higher than that in the general population. A relationship between risk of meningioma and exposure to ionizing radiation is also well known and led us to examine whether variants in DNA repair genes contribute to disease susceptibility.Methods: We analyzed 1127 tagging single-nucleotide polymorphisms (SNPs) that were selected to capture most of the common variation in 136 DNA repair genes in five case–control series (631 case patients and 637 control subjects) from four countries in Europe. We also analyzed 388 putative functional SNPs in these genes for their association with meningioma. All statistical tests were two-sided.Results: The SNP rs4968451, which maps to intron 4 of the gene that encodes breast cancer susceptibility gene 1–interacting protein 1, was consistently associated with an increased risk of developing meningioma. Across the five studies, the association was highly statistically significant (trend odds ratio = 1.57, 95% confidence interval = 1.28 to 1.93; Ptrend = 8.95 × 10−6; P = .009 after adjusting for multiple testing).Conclusions: We have identified a novel association between rs4968451 and meningioma risk. Because approximately 28% of the European population are carriers of at-risk genotypes for rs4968451, the variant is likely to make a substantial contribution to the development of meningioma.
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