| 1. |
- Andersson, Andreas, et al.
(författare)
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Public support for healthcare-mediated disclosure of hereditary cancer risk information: Results from a population-based survey in Sweden
- 2020
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Ingår i: Hereditary Cancer in Clinical Practice. - : Springer Science and Business Media LLC. - 1731-2302 .- 1897-4287. ; 18:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Targeted surveillance of at-risk individuals in families with increased risk of hereditary cancer is an effective prevention strategy if relatives are identified, informed and enrolled in screening programs. Despite the potential benefits, many eligible at-risk relatives remain uninformed of their cancer risk. This study describes the general public's opinion on disclosure of hereditary colorectal cancer (CRC) risk information, as well as preferences on the source and the mode of information. Methods A random sample of the general public was assessed through a Swedish citizen web-panel. Respondents were presented with scenarios of being an at-risk relative in a family that had an estimated increased hereditary risk of CRC; either 10% (moderate) or 70% (high) lifetime risk. A colonoscopy was presented as a preventive measure. Results were analysed to identify significant differences between groups using the Pearson's chi-square (chi(2)) test. Results Of 1800 invited participants, 977 completed the survey (54%). In the moderate and high-risk scenarios, 89.2 and 90.6% respectively, would like to receive information about a potential hereditary risk of CRC (chi 2,p = .755). The desire to be informed was higher among women (91.5%) than men (87.0%, chi 2,p = .044). No significant differences were found when comparing different age groups, educational levels, place of residence and having children or not. The preferred source of risk information was a healthcare professional in both moderate and high-risk scenarios (80.1 and 75.5%). However, 18.1 and 20.1% respectively would prefer to be informed by a family member. Assuming that healthcare professionals disclosed the information, the favoured mode of information was letter and phone (38.4 and 33.2%). Conclusions In this study a majority of respondents wanted to be informed about a potential hereditary risk of CRC and preferred healthcare professionals to communicate this information. The two presented levels of CRC lifetime risk did not significantly affect the interest in being informed. Our data offer insights into the needs and preferences of the Swedish population, providing a rationale for developing complementary healthcare-assisted communication pathways to realise the full potential of targeted prevention of hereditary CRC.
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| 2. |
- Brandefors, Lena, 1960-
(författare)
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Waldenstrom's macroglobulinemia : population based studies of familial aggregation and prognostic factors
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- BackgroundWaldenstrom’s macroglobulinemia (WM) is a rare lymphoproliferative disorder with a world-wide incidence of 3-4 patients per million persons per year. In Sweden, the incidence was about three times higher, and approximately 100 patients per year are reported to the Swedish Lymphoma Registry (SLR). Our aim was to study the WM population with focus on incidence and survival in relation to clinical prognostic factors and primary therapies (Paper I-II). We also discussed the diagnostic difficulties in patients with non-WM lymphoplasmacytic lymphoma (LPL). In Paper III-IV, we study familial WM from different aspects to better understand underlying pathogenetic factors.Patients and methodsThe patients in all four studies were collected from SLR. In papers I and II, a total of 1511 patients with WM and non-WM LPL were registered between 2000 and 2014, and medical records were retrieved for 1139 patients (75%). A retrospective review showed that 981 and 33 (after review by haematopathologist) of these patients fulfilled the World Health Organization (WHO) diagnostic criteria for WM and non-WM LPL, respectively. In Paper III and IV, we used SLR and the Northern Lymphoma Registry (NLR) for the years 1997- 2011. We identified 12 families with a family history of WM, IgM monoclonal gammopathy of undetermined significance (MGUS) and/or multiple myeloma (MM).ResultsIn paper I, the overall survival (OS) for WM improved between the two time periods, 2000-2006 and 2007-2014, with a five-year OS of 61% and 70%, respectively. Significant prognostic factors for OS at the time of diagnosis in asymptomatic patients in no need of therapy were age, poor performance status (PS), haemoglobin ≤115 g/l, and female sex. Elevated lactate dehydrogenase (LDH) level and haemoglobin ≤115 g/l were significant prognostic factors for patients receiving therapy 0-3 months after diagnosis. The level of the IgM monoclonal immunoglobulin (MI) had no significant prognostic value. Rituximab included in first-line therapy was associated with improved survival. Paper II describes the differential diagnostic difficulties in non-WM LPL, especially with Marginal Zone Lymphoma (MZL). The non-WM LPL patients had more adverse prognostic factors as elevated LDH, anaemia, and lymphocytosis at diagnosis compared to the patients with WM. Despite this, the OS did not significantly differ between the groups (P = 0.249). The median OS for non-WM LPL was 71 months and the three-year and five-year survival was 71 % and 55%, respectively. The OS and RS were worse for males than females. In Paper III, we showed that age-adjusted incidence in Norrbotten and Västerbotten for WM and non-WM LPL was higher than expected – 17.5 and 14.8 per million person and year, respectively. The corresponding figure for Sweden was 10.5 per million persons per year. Autoimmune diseases or haematological malignancies in the medical history in patients or in their relatives were reported in nine and five of the 12 families, respectively. The relatives showed a high proportion abnormal serum protein electrophoresis (SPE): 12/56 (21%) showed MGUS and 13/56 (25%) showed abnormalities in the immunoglobulin levels (i.e., subnormal levels and poly/oligoclonality). Paper IV describes hyperphosphorylated paratarg 7 (pP-7), a target of 11% of the monoclonal immunoglobulin M (IgM) in WM and MGUS of IgM type, and distribution in Sweden and in familial WM. The frequency of pP-7 seems to be in line or lower in non-familial WM (7.1%) and higher in familial WM (16.7%) in the counties of Norrbotten and Västerbotten than in earlier published studies. Positive analysis for pP-7 was shown up to 10 years before diagnosis of WM.ConclusionWe show that in a rare disease such as WM registry studies might bring new knowledge about incidence, disease characteristic, prognostic factors, treatments, and outcome. We also identified aggregation of families with WM in an effort to better understand the underlying pathogenesis
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| 3. |
- Dahlin, Anna M., 1979-, et al.
(författare)
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A genome-wide association study on medulloblastoma
- 2020
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Ingår i: Journal of Neuro-Oncology. - : Springer. - 0167-594X .- 1573-7373. ; 147:2, s. 309-315
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Medulloblastoma is a malignant embryonal tumor of the cerebellum that occurs predominantly in children. To find germline genetic variants associated with medulloblastoma risk, we conducted a genome-wide association study (GWAS) including 244 medulloblastoma cases and 247 control subjects from Sweden and Denmark.Methods: Genotyping was performed using Illumina BeadChips, and untyped variants were imputed using IMPUTE2.Results: Fifty-nine variants in 11 loci were associated with increased medulloblastoma risk (p < 1 × 10–5), but none were statistically significant after adjusting for multiple testing (p < 5 × 10–8). Thirteen of these variants were genotyped, whereas 46 were imputed. Genotyped variants were further investigated in a validation study comprising 249 medulloblastoma cases and 629 control subjects. In the validation study, rs78021424 (18p11.23, PTPRM) was associated with medulloblastoma risk with OR in the same direction as in the discovery cohort (ORT = 1.59, pvalidation = 0.02). We also selected seven medulloblastoma predisposition genes for investigation using a candidate gene approach: APC, BRCA2, PALB2, PTCH1, SUFU, TP53, and GPR161. The strongest evidence for association was found for rs201458864 (PALB2, ORT = 3.76, p = 3.2 × 10–4) and rs79036813 (PTCH1, ORA = 0.42, p = 2.6 × 10–3).Conclusion: The results of this study, including a novel potential medulloblastoma risk loci at 18p11.23, are suggestive but need further validation in independent cohorts.
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| 4. |
- Feng, Helian, et al.
(författare)
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Cross-cancer cross-tissue Transcriptome-wide Association Study (TWAS) of 11 cancers identifies 56 novel genes
- 2020
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Ingår i: Genetic Epidemiology. - : John Wiley & Sons. - 0741-0395 .- 1098-2272. ; 44:5, s. 481-481
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Though heterogeneous, multiple tumor types share hallmark mechanisms. Thus, identifying genes associated with multiple cancer types may shed light on general oncogenic mechanisms and identify genes missed in single‐cancer analyses. TWAS have been successful in testing whether genetically‐predicted tissue‐specific gene expression is associated with cancer risk. Although cross‐cancer genome‐wide association studies (GWAS) analyses have been performed previously, no cross‐cancer TWAS has been conducted to date. Here, we implement a pipeline to perform cross‐cancer, cross‐tissue TWAS analysis. We use newly‐developed multi‐trait TWAS test statistics to integrate the TWAS results for association between 11 separated cancers and predicted gene expression in 43 GTEx tissues, including a “sum” test and a “variance components” test, analogous to fixed‐ and random‐effects meta‐analyses. We then integrated the results across different tissues using the Aggregated Cauchy Association Test (ACAT) combined test.A total of 403 genes were significantly associated with at least one cancer type for at least one tissue; 96 additional genes were identified when combining test results across cancers; and 35 additional genes when further combining test results across tissue. Among these significant genes, 70 were not near previously‐published GWAS index variants. 14 of the 70 novel genes were identified from the single‐cancer single‐tissue test; an additional 43 were identified with the cross‐cancer test; and another 13 were identified when further combined across tissues. The newly identified genes, including RBBP8 and TP53BP , are involved in chromatin structure, tumorigenesis, apoptosis, transcriptional regulation, DNA repair, immune system, oxidative damage and cell‐cycle, proliferation, progression, shape, structure, and migration.
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| 5. |
- Jonsson, Pär, et al.
(författare)
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Identification of Pre-Diagnostic Metabolic Patterns for Glioma Using Subset Analysis of Matched Repeated Time Points
- 2020
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Ingår i: Cancers. - : MDPI. - 2072-6694. ; 12:11
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Tidskriftsartikel (refereegranskat)abstract
- Simple Summary: Reprogramming of cellular metabolism is a major hallmark of cancer cells, and play an important role in tumor initiation and progression. The aim of our study is to discover circulating early metabolic markers of brain tumors, as discovery and development of reliable predictive molecular markers are needed for precision oncology applications. We use a study design tailored to minimize confounding factors and a novel machine learning and visualization approach (SMART) to identify a panel of 15 interlinked metabolites related to glioma development. The presented SMART strategy facilitates early molecular marker discovery and can be used for many types of molecular data.Abstract: Here, we present a strategy for early molecular marker pattern detection-Subset analysis of Matched Repeated Time points (SMART)-used in a mass-spectrometry-based metabolomics study of repeated blood samples from future glioma patients and their matched controls. The outcome from SMART is a predictive time span when disease-related changes are detectable, defined by time to diagnosis and time between longitudinal sampling, and visualization of molecular marker patterns related to future disease. For glioma, we detect significant changes in metabolite levels as early as eight years before diagnosis, with longitudinal follow up within seven years. Elevated blood plasma levels of myo-inositol, cysteine, N-acetylglucosamine, creatinine, glycine, proline, erythronic-, 4-hydroxyphenylacetic-, uric-, and aceturic acid were particularly evident in glioma cases. We use data simulation to ensure non-random events and a separate data set for biomarker validation. The latent biomarker, consisting of 15 interlinked and significantly altered metabolites, shows a strong correlation to oxidative metabolism, glutathione biosynthesis and monosaccharide metabolism, linked to known early events in tumor development. This study highlights the benefits of progression pattern analysis and provide a tool for the discovery of early markers of disease.
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| 6. |
- Lupo, Philip J., et al.
(författare)
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Perinatal and familial risk factors for soft tissue sarcomas in childhood through young adulthood : a population-based assessment in 4 million live births
- 2020
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Ingår i: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 146:3, s. 791-802
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Tidskriftsartikel (refereegranskat)abstract
- Perinatal factors have been associated with soft tissue sarcomas (STS) in case-control studies. However, (i) the contributions of factors including fetal growth remain unknown, (ii) these factors have not been examined in cohort studies and (iii) few assessments have evaluated risk in specific STS subtypes. We sought to identify the role of perinatal and familial factors on the risk of STS in a large population-based birth cohort. We identified 4,023,436 individuals in the Swedish Birth Registry born during 1973-2012. Subjects were linked to the Swedish Cancer Registry, where incident STS cases were identified. We evaluated perinatal and familial factors obtained from Statistics Sweden, including fetal growth, gestational age, and presence of a congenital malformation. Poisson regression was used to estimate incidence rate ratios (IRRs) and 95% confidence intervals (CIs) for associations between perinatal factors and STS overall, as well as by common subtypes. There were 673 individuals diagnosed with STS in 77.5 million person-years of follow-up. Having a congenital malformation was associated with STS (IRR = 1.70, 95% CI: 1.23-2.35). This association was stronger (IRR = 2.90, 95% CI: 1.25-6.71) in recent years (2000-2012). Low fetal growth was also associated with STS during the same time period (IRR = 1.86, 95% CI: 1.05-3.29). Being born preterm was associated with rhabdomyosarcoma (IRR = 1.74, 95% CI: 1.08-2.79). In our cohort study, those with congenital malformations and other adverse birth outcomes were more likely to develop a STS compared to their unaffected contemporaries. These associations may point to disrupted developmental pathways and genetic factors influencing the risk of STS.
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| 7. |
- Ostrom, Quinn T., et al.
(författare)
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Glioma risk associated with extent of estimated European genetic ancestry in African Americans and Hispanics
- 2020
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Ingår i: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 146:3, s. 739-748
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Tidskriftsartikel (refereegranskat)abstract
- Glioma incidence is highest in non-Hispanic Whites, and to date, glioma genome-wide association studies (GWAS) to date have only included European ancestry (EA) populations. African Americans and Hispanics in the US have varying proportions of EA, African (AA) and Native American ancestries (NAA). It is unknown if identified GWAS loci or increased EA is associated with increased glioma risk. We assessed whether EA was associated with glioma in African Americans and Hispanics. Data were obtained for 832 cases and 675 controls from the Glioma International Case-Control Study and GliomaSE Case-Control Study previously estimated to have <80% EA, or self-identify as non-White. We estimated global and local ancestry using fastStructure and RFMix, respectively, using 1,000 genomes project reference populations. Within groups with >= 40% AA (AFR(>= 0.4)), and >= 15% NAA (AMR(>= 0.15)), genome-wide association between local EA and glioma was evaluated using logistic regression conditioned on global EA for all gliomas. We identified two regions (7q21.11, p = 6.36 x 10(-4); 11p11.12, p = 7.0 x 10-4) associated with increased EA, and one associated with decreased EA (20p12.13, p = 0.0026) in AFR(>= 0.4). In addition, we identified a peak at rs1620291 (p = 4.36 x 10(-6)) in 7q21.3. Among AMR(>= 0.15), we found an association between increased EA in one region (12q24.21, p = 8.38 x 10(-4)), and decreased EA in two regions (8q24.21, p = 0. 0010; 20q13.33, p = 6.36 x 10(-4)). No other significant associations were identified. This analysis identified an association between glioma and two regions previously identified in EA populations (8q24.21, 20q13.33) and four novel regions (7q21.11, 11p11.12, 12q24.21 and 20p12.13). The identifications of novel association with EA suggest regions to target for future genetic association studies. What's new? Glioma is rare in non-White populations, and most glioma genome-wide association studies have included only primarily European ancestry populations. Here, the authors assess whether variation in European ancestry is associated with glioma risk in populations with a combination of European, African and Native American ancestry. Based on African American and Hispanic cases from two large glioma case-control studies, this analysis shows that increased European ancestry in admixed populations may be associated with increased glioma risk. The associations between glioma and two chromosomal regions previously identified in European ancestry populations, and four novel regions, may guide future studies.
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| 8. |
- Saunders, Charlie N., et al.
(författare)
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Lack of association between modifiable exposures and glioma risk : a Mendelian randomization analysis
- 2020
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Ingår i: Neuro-Oncology. - : OXFORD UNIV PRESS INC. - 1522-8517 .- 1523-5866. ; 22:2, s. 207-215
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Forskningsöversikt (refereegranskat)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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| 9. |
- Sjöström, Olle, et al.
(författare)
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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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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 15:8
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Tidskriftsartikel (refereegranskat)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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| 10. |
- Svensson, Daniel, et al.
(författare)
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A whole-genome sequenced control population in northern Sweden reveals subregional genetic differences
- 2020
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Ingår i: PLOS ONE. - : Public Library Science. - 1932-6203. ; 15:9
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Tidskriftsartikel (refereegranskat)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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