| 21. |
- Rentoft, Matilda, et al.
(author)
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Robusta biomarkörer för prediktion av risk och sjukdom : en utvärdering av reproducerbarheten hos de stora kommersiella omik-plattformarna
- 2022
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Reports (pop. science, debate, etc.)abstract
- I och med utveckling inom storskalig analys av blodprover har man idag insett nyttan av att omvandla biobanker med lagrade humanprover till data-banker där forskare snabbt kan få tillgång till data för att svara på forsknings-frågor. Problemet är att många av teknikerna för att skapa storskaliga data är semikvantitativa, värdena går inte att relatera till en absolut koncentration och är därmed svåra att slå samman och jämföra över tid. Randomisering, det vill säga att proverna analyseras i slumpvis inbördes ordning, är en av de viktigas-te aspekterna för att skapa data som går att slå samman och återanvända för många forskningsfrågor. Detta underlättar korrigering av oönskade analysva-riationer över tid. Utöver detta kan man använda sig av bryggningsprover, QC-prov (kvalitetskontrollprov) eller ankarprover, som analyseras upprepat både inom och mellan analystillfällen, vilket underlättar att lägga samman dataset som analyseras vid olika tillfällen.Många kommersiella analysplattformar inkluderar ett eget QC-prov i analysen och vissa delar med sig av data för dessa prover. Det vore värdefullt om alla plattformar delade dessa data för kvalitetsutvärdering och eventuell korrige-ring av analysvariationer över tid. För alla semikvantitativa plattformar som undersöktes (Olink, Somalogic, Metabolon och Biocrates) var den tekniska variabiliteten mellan QC-proverna betydligt lägre än variabiliteten mellan ana-lyserade plasmaprover. Detta var tydligast för proteomikplattformarna, vilket antyder att förutsättningarna att upptäcka biologiska skillnader är bättre i pro-teomikdata. Undantaget från detta är en femte plattform, Nightingale, en kvan-titativ men smalare metabololmikmetod som anses generera stabila mätningar.Vid all utveckling av biomarkörpaneler för att prediktera sjukdom behöver man göra upptäcktsanalyser, sedan valideringsstudier och därefter tester i den situation man tänker att testet ska fungera. De breda omikplattformarna läm-par sig för upptäckt och eventuellt validering, men för det faktiska kliniska tes-tet behövs en kvantitativ analys för att verkligen utvärdera att de proteiner eller metaboliter man vill använda är stabilt uppmätbara och fungerar för att pre-diktera sjukdom eller risk för sjukdom.
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| 22. |
- Rosenbaum, Adam, et al.
(author)
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Low-grade glioma risk SNP rs11706832 is associated with type I interferon response pathway genes in cell lines
- 2023
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In: Scientific Reports. - : Springer Nature. - 2045-2322. ; 13
-
Journal article (peer-reviewed)abstract
- Genome-wide association studies (GWAS) have contributed to our understanding of glioma susceptibility. To date, 25 risk loci for development of any of the glioma subtypes are known. However, GWAS studies reveal little about the molecular processes that lead to increased risk, especially for non-coding single nucleotide polymorphisms (SNP). A particular SNP in intron 2 of LRIG1, rs11706832, has been shown to increase the susceptibility for IDH1 mutated low-grade gliomas (LGG). Leucine-rich repeats and immunoglobulin-like domains protein 1 (LRIG1) is important in cancer development as it negatively regulates the epidermal growth factor receptor (EGFR); however, the mechanism responsible for this particular risk SNP and its potential effect on LRIG1 are not known. Using CRISPR-CAS9, we edited rs11706832 in HEK293T cells. Four HEK293T clones with the risk allele were compared to four clones with the non-risk allele for LRIG1 and SLC25A26 gene expression using RT-qPCR, for global gene expression using RNA-seq, and for metabolites using gas chromatography-mass spectrometry (GC–MS). The experiment did not reveal any significant effect of the SNP on the expression levels or splicing patterns of LRIG1 or SLC25A26. The global gene expression analysis revealed that the risk allele C was associated with upregulation of several mitochondrial genes. Gene enrichment analysis of 74 differentially expressed genes in the genome revealed a significant enrichment of type I interferon response genes, where many genes were downregulated for the risk allele C. Gene expression data of IDH1 mutated LGGs from the cancer genome atlas (TCGA) revealed a similar under expression of type I interferon genes associated with the risk allele. This study found the expression levels and splicing patterns of LRIG1 and SLC25A26 were not affected by the SNP in HEK293T cells. However, the risk allele was associated with a downregulation of genes involved in the innate immune response both in the HEK293T cells and in the LGG data from TCGA.
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| 23. |
- Saunders, Charlie N., et al.
(author)
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Lack of association between modifiable exposures and glioma risk : a Mendelian randomization analysis
- 2020
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In: Neuro-Oncology. - : OXFORD UNIV PRESS INC. - 1522-8517 .- 1523-5866. ; 22:2, s. 207-215
-
Research review (peer-reviewed)abstract
- Background. The etiological basis of glioma is poorly understood. We have used genetic markers in a Mendelian randomization (MR) framework to examine if lifestyle, cardiometabolic, and inflammatory factors influence the risk of glioma. This methodology reduces bias from confounding and is not affected by reverse causation. Methods. We identified genetic instruments for 37 potentially modifiable risk factors and evaluated their association with glioma risk using data from a genome-wide association study of 12488 glioma patients and 18169 controls. We used the estimated odds ratio of glioma associated with each of the genetically defined traits to infer evidence for a causal relationship with the following exposures: Lifestyle and dietary factors-height, plasma insulin-like growth factor 1, blood carnitine, blood methionine, blood selenium, blood zinc, circulating adiponectin, circulating carotenoids, iron status, serum calcium, vitamins (A1, B12, B6, E, and 25-hydroxyvitamin D), fatty acid levels (monounsaturated, omega-3, and omega-6) and circulating fetuin-A; Cardiometabolic factors-birth weight, high density lipoprotein cholesterol, low density lipoprotein cholesterol, total cholesterol, total triglycerides, basal metabolic rate, body fat percentage, body mass index, fasting glucose, fasting proinsulin, glycated hemoglobin levels, diastolic and systolic blood pressure, waist circumference, waist-to-hip ratio; and Inflammatory factors- C-reactive protein, plasma interleukin-6 receptor subunit alpha and serum immunoglobulin E. Results. After correction for the testing of multiple potential risk factors and excluding associations driven by one single nucleotide polymorphism, no significant association with glioma risk was observed (ie, P-Corrected > 0.05). Conclusions. This study did not provide evidence supporting any of the 37 factors examined as having a significant influence on glioma risk.
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| 24. |
- Sjöström, Olle, et al.
(author)
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Travel time to care does not affect survival for patients with colorectal cancer in northern Sweden : A data linkage study from the Risk North database
- 2020
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In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 15:8
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Journal article (peer-reviewed)abstract
- INTRODUCTION: Numerous prior studies, even from countries with free access to care, have associated long travel time to care with poor survival in patients with colorectal cancer. METHODS: This is a data-linkage study of all 3718 patients with colorectal cancer, diagnosed between 2007 and 2013 in Northern Sweden, one of the most sparsely populated areas in Europe. Travel time to nearest hospital was calculated based on GPS coordinates and multivariable Cox regression was used to analyse possible associations between travel time and cause-specific survival. RESULTS: No association between travel time and survival was observed, either in univariable analysis (colon HR 1.00 [95% CI 0.998-1.003]; rectal HR 0.998; [95% CI 0.995-1.002]) or in multivariable Cox regression analysis (colon HR 0.999 [95% CI 0.997-1.002]; rectal HR 0.997 [95% CI 0.992-1.002]). CONCLUSIONS: In contrast to most other studies, no association between travel time and colorectal cancer survival was found; despite that longer travel time was associated with known risk factors for poorer outcome. In the Swedish health care setting, travel time does not appear to represent a barrier to care or to negatively influence outcomes.
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| 25. |
- Svensson, Daniel, et al.
(author)
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A whole-genome sequenced control population in northern Sweden reveals subregional genetic differences
- 2020
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In: PLOS ONE. - : Public Library Science. - 1932-6203. ; 15:9
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Journal article (peer-reviewed)abstract
- The number of national reference populations that are whole-genome sequenced are rapidly increasing. Partly driving this development is the fact that genetic disease studies benefit from knowing the genetic variation typical for the geographical area of interest. A whole-genome sequenced Swedish national reference population (n = 1000) has been recently published but with few samples from northern Sweden. In the present study we have whole-genome sequenced a control population (n = 300) (ACpop) from Västerbotten County, a sparsely populated region in northern Sweden previously shown to be genetically different from southern Sweden. The aggregated variant frequencies within ACpop are publicly available (DOI 10.17044/NBIS/G000005) to function as a basic resource in clinical genetics and for genetic studies. Our analysis of ACpop, representing approximately 0.11% of the population in Västerbotten, indicates the presence of a genetic substructure within the county. Furthermore, a demographic analysis showed that the population from which samples were drawn was to a large extent geographically stationary, a finding that was corroborated in the genetic analysis down to the level of municipalities. Including ACpop in the reference population when imputing unknown variants in a Västerbotten cohort resulted in a strong increase in the number of high-confidence imputed variants (up to 81% for variants with minor allele frequency < 5%). ACpop was initially designed for cancer disease studies, but the genetic structure within the cohort will be of general interest for all genetic disease studies in northern Sweden.
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| 26. |
- Wendt, Camilla, et al.
(author)
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A search for modifying genetic factors in CHEK2:c.1100delC breast cancer patients
- 2021
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11, s. 1-9
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Journal article (peer-reviewed)abstract
- The risk of breast cancer associated with CHEK2:c.1100delC is 2-threefold but higher in carriers with a family history of breast cancer than without, suggesting that other genetic loci in combination with CHEK2:c.1100delC confer an increased risk in a polygenic model. Part of the excess familial risk has been associated with common low-penetrance variants. This study aimed to identify genetic loci that modify CHEK2:c.1100delC-associated breast cancer risk by searching for candidate risk alleles that are overrepresented in CHEK2:c.1100delC carriers with breast cancer compared with controls. We performed whole-exome sequencing in 28 breast cancer cases with germline CHEK2:c.1100delC, 28 familial breast cancer cases and 70 controls. Candidate alleles were selected for validation in larger cohorts. One recessive synonymous variant, rs16897117, was suggested, but no overrepresentation of homozygous CHEK2:c.1100delC carriers was found in the following validation. Furthermore, 11 non-synonymous candidate alleles were suggested for further testing, but no significant difference in allele frequency could be detected in the validation in CHEK2:c.1100delC cases compared with familial breast cancer, sporadic breast cancer and controls. With this method, we found no support for a CHEK2:c.1100delC-specific genetic modifier. Further studies of CHEK2:c.1100delC genetic modifiers are warranted to improve risk assessment in clinical practice.
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| 27. |
- Wu, Wendy Yi-Ying, et al.
(author)
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Assessment of the EarlyCDT-Lung test as an early biomarker of lung cancer in ever-smokers : A retrospective nested case-control study in two prospective cohorts
- 2023
-
In: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 152:9, s. 2002-2010
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Journal article (peer-reviewed)abstract
- The EarlyCDT-Lung test is a blood-based autoantibody assay intended to identify high-risk individuals for low-dose computed tomography lung cancer screening. However, there is a paucity of evidence on the performance of the EarlyCDT-Lung test in ever-smokers. We conducted a nested case-control study within two prospective cohorts to evaluate the risk-discriminatory performance of the EarlyCDT-Lung test using prediagnostic blood samples from 154 future lung cancer cases and 154 matched controls. Cases were selected from those who had ever smoked and had a prediagnostic blood sample <3 years prior to diagnosis. Conditional logistic regression was used to estimate the association between EarlyCDT-Lung test results and lung cancer risk. Sensitivity and specificity of the EarlyCDT-Lung test were calculated in all subjects and subgroups based on age, smoking history, lung cancer stage, sample collection time before diagnosis and year of sample collection. The overall lung cancer odds ratios were 0.89 (95% CI: 0.34-2.30) for a moderate risk EarlyCDT-Lung test result and 1.09 (95% CI: 0.48-2.47) for a high-risk test result compared to no significant test result. The overall sensitivity was 8.4% (95% CI: 4.6-14) and overall specificity was 92% (95% CI: 87-96) when considering a high-risk result as positive. Stratified analysis indicated higher sensitivity (17%, 95% CI: 7.2-32.1) in subjects with blood drawn up to 1 year prior to diagnosis. In conclusion, our study does not support a role of the EarlyCDT-Lung test in identifying the high-risk subjects in ever-smokers for lung cancer screening in the EPIC and NSHDS cohorts.
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| 28. |
- Wu, Wendy Yi-Ying, et al.
(author)
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Pre-diagnostic levels of sVEGFR2, sTNFR2, sIL-2Rα and sIL-6R are associated with glioma risk : A nested case–control study of repeated samples
- 2022
-
In: Cancer Medicine. - : John Wiley & Sons. - 2045-7634. ; 11:4, s. 1016-1025
-
Journal article (peer-reviewed)abstract
- No strong aetiological factors have been established for glioma aside from genetic mutations and variants, ionising radiation and an inverse relationship with asthmas and allergies. Our aim was to investigate the association between pre-diagnostic immune protein levels and glioma risk. We conducted a case–control study nested in the Northern Sweden Health and Disease Study cohort. We analysed 133 glioma cases and 133 control subjects matched by age, sex and date of blood donation. ELISA or Luminex bead-based multiplex assays were used to measure plasma levels of 19 proteins. Conditional logistic regression models were used to estimate the odds ratios and 95% CIs. To further model the protein trajectories over time, the linear mixed-effects models were conducted. We found that the levels of sVEGFR2, sTNFR2, sIL-2Rα and sIL-6R were associated with glioma risk. After adjusting for the time between blood sample collection and glioma diagnosis, the odds ratios were 1.72 (95% CI = 1.01–2.93), 1.48 (95% CI = 1.01–2.16) and 1.90 (95% CI = 1.14–3.17) for sTNFR2, sIL-2Rα and sIL-6R, respectively. The trajectory of sVEGFR2 concentrations over time was different between cases and controls (p-value = 0.031), increasing for cases (0.8% per year) and constant for controls. Our findings suggest these proteins play important roles in gliomagenesis.
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| 29. |
- Wu, Wendy Yi-Ying, et al.
(author)
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Prediagnostic biomarkers for early detection of glioma : using case-control studies from cohorts as study approach
- 2022
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In: Neuro-Oncology Advances. - : Oxford University Press. - 2632-2498. ; 4, s. II73-II80
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Journal article (peer-reviewed)abstract
- Background: Understanding the trajectory and development of disease is important and the knowledge can be used to find novel targets for therapy and new diagnostic tools for early diagnosis.Methods: Large cohorts from different parts of the world are unique assets for research as they have systematically collected plasma and DNA over long-time periods in healthy individuals, sometimes even with repeated samples. Over time, the population in the cohort are diagnosed with many different diseases, including brain tumors.Results: Recent studies have detected genetic variants that are associated with increased risk of glioblastoma and lower grade gliomas specifically. The impact for genetic markers to predict disease in a healthy population has been deemed low, and a relevant question is if the genetic variants for glioma are associated with risk of disease or partly consist of genes associated to survival. Both metabolite and protein spectra are currently being explored for early detection of cancer.Conclusions: We here present a focused review of studies of genetic variants, metabolomics, and proteomics studied in prediagnostic glioma samples and discuss their potential in early diagnostics.
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| 30. |
- Zhang, YD, et al.
(author)
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Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers
- 2020
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1, s. 3353-
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Journal article (peer-reviewed)abstract
- Genome-wide association studies (GWAS) have led to the identification of hundreds of susceptibility loci across cancers, but the impact of further studies remains uncertain. Here we analyse summary-level data from GWAS of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) and underlying effect-size distribution. All cancers show a high degree of polygenicity, involving at a minimum of thousands of loci. We project that sample sizes required to explain 80% of GWAS heritability vary from 60,000 cases for testicular to over 1,000,000 cases for lung cancer. The maximum relative risk achievable for subjects at the 99th risk percentile of underlying polygenic risk scores (PRS), compared to average risk, ranges from 12 for testicular to 2.5 for ovarian cancer. We show that PRS have potential for risk stratification for cancers of breast, colon and prostate, but less so for others because of modest heritability and lower incidence.
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