| 1. |
- Haas, Jan, et al.
(author)
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Atlas of the clinical genetics of human dilated cardiomyopathy
- 2015
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In: European Heart Journal. - : Oxford University Press. - 0195-668X .- 1522-9645. ; 36:18, s. 1123-U43
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Journal article (peer-reviewed)abstract
- Aim: We were able to show that targeted Next-Generation Sequencing is well suited to be applied in clinical routine diagnostics, substantiating the ongoing paradigm shift from low- to high-throughput genomics in medicine. By means of our atlas of the genetics of human DCM, we aspire to soon be able to apply our findings to the individual patient with cardiomyopathy in daily clinical practice. Numerous genes are known to cause dilated cardiomyopathy (DCM). However, until now technological limitations have hindered elucidation of the contribution of all clinically relevant disease genes to DCM phenotypes in larger cohorts. We now utilized next-generation sequencing to overcome these limitations and screened all DCM disease genes in a large cohort. Methods and results: In this multi-centre, multi-national study, we have enrolled 639 patients with sporadic or familial DCM. To all samples, we applied a standardized protocol for ultra-high coverage next-generation sequencing of 84 genes, leading to 99.1% coverage of the target region with at least 50-fold and a mean read depth of 2415. In this well characterized cohort, we find the highest number of known cardiomyopathy mutations in plakophilin-2, myosin-binding protein C-3, and desmoplakin. When we include yet unknown but predicted disease variants, we find titin, plakophilin-2, myosin-binding protein-C 3, desmoplakin, ryanodine receptor 2, desmocollin-2, desmoglein-2, and SCN5A variants among the most commonly mutated genes. The overlap between DCM, hypertrophic cardiomyopathy (HCM), and channelopathy causing mutations is considerably high. Of note, we find that >38% of patients have compound or combined mutations and 12.8% have three or even more mutations. When comparing patients recruited in the eight participating European countries we find remarkably little differences in mutation frequencies and affected genes. Conclusion: This is to our knowledge, the first study that comprehensively investigated the genetics of DCM in a large-scale cohort and across a broad gene panel of the known DCM genes. Our results underline the high analytical quality and feasibility of Next-Generation Sequencing in clinical genetic diagnostics and provide a sound database of the genetic causes of DCM.
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| 2. |
- Bermejo, Justo Lorenzo, et al.
(author)
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Age-time risk patterns of solid cancers in 60 901 non-Hodgkin lymphoma survivors from Finland, Norway and Sweden
- 2014
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In: British Journal of Haematology. - : Wiley. - 0007-1048. ; 164:5, s. 675-683
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Journal article (peer-reviewed)abstract
- Survival after non-Hodgkin lymphoma (NHL) has increased thanks to improved treatment but NHL survivors have an increased risk of second neoplasms. The assessment of cancer risk patterns after NHL may help to quantify the late side-effects of therapy. Poisson regression was used to estimate relative risks (RRs) and absolute incidence rates for nine solid tumours based on a nationwide cohort of 60 901 NHL survivors from Finland, Norway and Sweden. Patients were diagnosed between 1980 and 2006 and developed 6815 s neoplasms. NHL patients showed an increased risk of each of the nine investigated cancer sites: prostate and pancreas (both RRs 1.28), breast (1.37), colorectum (1.48), urinary bladder (1.52), stomach and lung (both RRs 1.87), skin (melanoma 2.27) and kidney (2.56). The RRs showed a U-shaped relationship with time after NHL for all nine-second cancer types. NHL diagnosis early in life was a risk factor for the development of second cancers with the exception of melanoma, but a risk excess was even observed in patients diagnosed with NHL at age 80+ years. The present study provides accurate estimates on the adverse late effects of NHL therapy, which should guide the establishment of cancer prevention strategies in NHL survivors.
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| 3. |
- Brandt, Andreas, et al.
(author)
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Age at Diagnosis and Age at Death in Familial Prostate Cancer
- 2009
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In: The Oncologist. - : Oxford University Press (OUP). - 1083-7159 .- 1549-490X. ; 14:12, s. 1209-1217
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Journal article (peer-reviewed)abstract
- Objectives. A family history of prostate cancer is associated with a higher risk for prostate cancer to first-degree relatives. If greater surveillance of men at familial risk is considered to be useful, population-based estimates of the differences in the age at diagnosis between familial and sporadic prostate cancer cases are needed. Methods. The men in the nationwide Swedish Family-Cancer Database were classified according to the number and type of affected first-degree relatives (father or brother) and according to the relative's age at diagnosis. The cumulative incidence of prostate cancer and cumulative prostate cancer-specific mortality were estimated using a stratified Cox model. Results. The cumulative incidence was highest for men with multiple affected first-degree relatives, and it was higher for brothers than for sons of prostate cancer patients. The age to reach the same cumulative incidence as the general population at age 55 years decreased with decreasing age at diagnosis of the relative, ranging from 48.7 years (father diagnosed before 60 years of age) to 53.7 years (father diagnosed after 82 years of age). Prostate cancer-specific mortality was also related to the number and type of affected relatives but there was no clear evidence for a dependency on the age at diagnosis of the relative. Conclusions. Men with a father or a brother affected by prostate cancer are diagnosed and die at earlier ages than men without a family history of prostate cancer. This study should encourage further analysis in order to assess the risks and benefits of screening for prostate cancer in men at higher risk. The Oncologist 2009; 14: 1209-1217
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| 4. |
- Brandt, Andreas, et al.
(author)
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Age-Specific Risk of Incident Prostate Cancer and Risk of Death from Prostate Cancer Defined by the Number of Affected Family Members
- 2010
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In: European Urology. - : Elsevier BV. - 1873-7560 .- 0302-2838. ; 58:2, s. 275-280
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Journal article (peer-reviewed)abstract
- Background: The thorough assessment of familial prostate cancer (PCa) risk is as important as ever to provide a basis for clinical counselling and screening recommendations. Objective: Our aim was to determine the age-specific risks of PCa and the risk of death from PCa according to the number and the age of affected first-degree relatives. Design, setting, and participants: The nationwide Swedish Family-Cancer Database includes a record of >11.8 million individuals and their cancers from 1958 to 2006. All men from the database with identified parents (>3.9 million individuals) were followed between 1961 and 2006. The study included 26 651 PCa patients, of whom 5623 were familial. Measurements: The age-specific hazard ratios (HRs) of PCa and the HRs of death from PCa were calculated according to the number and age of affected fathers and brothers. Results and limitations: The HRs of PCa diagnosis increased with the number of affected relatives and decreased with increasing age. The highest HRs were observed for men <65 yr of age with three affected brothers (HR: approximately 23) and the lowest for men between 65 and 74 yr of age with an affected father (HR: approximately 1.8). The HRs increased with decreasing paternal or fraternal diagnostic age. The pattern of the risk of death from familial PCa was similar to the incidence data. Conclusions: The present results should guide clinical counselling and demonstrate the vast increases in risk when multiple first-degree relatives are affected. (C) 2010 European Association of Urology. Published by Elsevier B.V. All rights reserved.
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| 5. |
- Brandt, Andreas, et al.
(author)
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Breast cancer risk in women who fulfill high-risk criteria: at what age should surveillance start?
- 2010
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In: Breast Cancer Research and Treatment. - : Springer Science and Business Media LLC. - 1573-7217 .- 0167-6806. ; 121:1, s. 133-141
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Journal article (peer-reviewed)abstract
- Family history is a strong predictor of hereditary breast cancer, particularly when it includes cases of early onset or bilateral breast cancers and multiple cases of breast or ovarian cancers. This article provides relative risks and cumulative risks of breast cancer in women whose family history indicates high risk. Specifically, the aim was to determine how many years earlier the high-risk women reach the cumulative risk of women without family history at the age at which screening in average-risk women is initiated. The women of the nation-wide Swedish Family-Cancer Database were classified according to clinical criteria based on family history suggesting high risk for hereditary breast ovarian cancer syndrome. The relative risks of breast cancer were calculated as hazard ratio using Cox regression. Cumulative risks of breast cancer were estimated with a stratified Cox model based on Tsiatis' method. The hazard ratios of breast cancer for the considered criteria ranged from 1.50 to 5.99. The cumulative risks ranged from 1 to 10% by age 50 years. The age to reach the same cumulative risk as women lacking a family history at the age of 50 years ranged between 32.0 and 40.8 years. Relative and cumulative risks of women at high risk of breast cancer associated with different clinical criteria were diverse, which may be helpful in considering when current clinical criteria are revised. According to the present results, current recommendations of starting clinical interventions 10 years earlier in high-risk women, based on expert opinions, appear justified at least for the largest high-risk groups.
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| 6. |
- Brandt, Andreas, et al.
(author)
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Familial risks of breast and prostate cancers: Does the definition of the at risk period matter?
- 2010
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In: European Journal of Cancer. - : Elsevier BV. - 1879-0852 .- 0959-8049. ; 46:4, s. 752-757
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Journal article (peer-reviewed)abstract
- Aim: 'Being at familial risk' may have different connotations in studies on familial risk of cancer. The register-based definition of a family history considers individuals with an affected relative at familial risk independently of the family member's diagnostic time. Alternatively, the individuals are classified to be at familial risk only after the diagnosis date of their relative, relevant to clinical counselling and screening situations. The aim of this study was to compare familial breast and prostate cancer risks according to the two definitions. Patients and methods: The nationwide Swedish Family-Cancer Database with information on cancers from 1958 to 2006 was used to calculate the hazard ratio of breast and prostate cancers according to family history using Cox regression. Family history was defined considering the number and type of affected relatives and the relative's diagnostic age, respectively. Individuals were considered at familial risk from their entry to the study or, alternatively, from the diagnostic time of the relative. Results: Hazard ratios were equal whether individuals were considered at risk independent of the relative's diagnostic date or only after the relative's diagnostic date. Conclusion: These results indicate that studies on familial breast or prostate cancer risk which do not take the relative's diagnosis date into account are applicable to screening and clinical counselling situations. The estimates according to the register-based definition are based on larger numbers of patients, which may be crucial for analysis of small groups such as families of multiple cases. (C) 2009 Elsevier Ltd. All rights reserved.
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| 7. |
- Castro, Felipe A, et al.
(author)
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Association of HLA-DRB1, interleukin-6 and cyclin D1 polymorphisms with cervical cancer in the Swedish population-A candidate gene approach.
- 2009
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In: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 125:8, s. 1851-1858
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Journal article (peer-reviewed)abstract
- High-risk human papillomavirus (hrHPV) infection is the major risk factor for cervical cancer (CxCa). The role of genetic susceptibility in the disease has been suggested, but the existing data lack consistency. We conducted a nested case-control study on 973 CxCa cases and 1,763 matched controls, from two Swedish population-based cohorts to examine the association of common genetic variants with CxCa risk. Human leukocyte antigen (HLA) alleles and 24 other polymorphisms in 14 genes were selected on the basis of reported association or mechanistic plausibility with an HPV infection or cervical cancer development. Genotyping was conducted using multiplex PCR and Luminex technology. A significant association of CxCa with various polymorphisms was observed: rs1800797 in the IL-6 gene (odds ratio [OR] = 0.88, 95% confidence intervals [CI]: 0.79-0.99); rs1041981 in the LTA gene (OR = 0.87, 95% CI: 0.78-0.98), and rs9344 in the CCND1 gene (OR = 1.14, 95% CI: 1.02-1.27), for those individuals carrying the rare allele. Additionally, the alleles 0401 and 1501 of the HLA class II DRB1 locus were associated with an increased risk (OR = 1.23, 95% CI: 1.04-1.45 and OR = 1.29, 95% CI: 1.11-1.50, respectively), and allele 1301 was associated with decreased risk (OR = 0.59, 95% CI: 0.47-0.73). The effects of CCND1 and the HLA*DRB1 alleles were independent of the effect of smoking. We did not find any association of risk with polymorphisms in genes related to the innate immune system. In conclusion, our study provides evidence for genetic susceptibility to CxCa due to variations in genes involved in the immune system and in cell cycle. (c) 2009 UICC.
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| 8. |
- de Verdier, Petra J., et al.
(author)
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Genotypes, haplotypes and diplotypes of three XPC polymorphisms in urinary-bladder cancer patients
- 2010
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In: Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis. - : Elsevier BV. - 1879-2871 .- 0027-5107. ; 694:1-2, s. 39-44
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Journal article (peer-reviewed)abstract
- Purpose The XPC gene is involved in DNA damage recognition in the nucleotide excision repair pathway (NER) We investigated the additive effects of single nucleotide polymorphisms (SNPs) in bladder-cancer patients and population controls for three XPC polymorphisms A499V (C>T) K939Q (A>C) and poly AT (PAT -/+) Experimental Design 311 bladder-cancer patients from a population-based cohort and 337 population controls were genotyped using the PCR-restriction fragment length polymorphism (RFLP) technique Results We found complete linkage between the K939Q (A>C) and PAT (-/+) polymorphisms and therefore only the K939Q (A>C) polymorphism was included in analyses The over all estimated odds ratio was 1 7 (95% CI 1 3-2 4) for A499V (C>T) and 1 4 (95% CI 1 0-2 0) for K939Q (A>C) The associated odds ratio Increase with the variant allele homozygotes was six-fold for the A499V (C>T) and three-fold for the K939Q (A>C) polymorphism (OR=5 7 95% CI 3 4-9 5 and OR=2 6 95% CI 1 3-5 6 respectively) The variant allele haplotype of the two polymorphisms (T499C939) was associated with a nearly four fold increased odds ratio compared to the common allele haplotype (C(499)A(939)) (OR=3 6 95% Cl 1 9-6 9) Combined genotype analysis showed an Increased disease association with increasing number of variant alleles (p<0 0001) with a dominant effect of the A499V polymorphism In addition we observed association of the disease with increasing number of variant alleles for the A499V polymorphism and an early age at diagnosis (p=0 004) Conclusions Our results suggest an association between the XPC genotypes of the A499V K939Q and PAT polymorphisms and urinary-bladder cancer We propose a poly-allelic effect of these polymorphisms where the cumulative effect on disease becomes higher than the individual allelic effects (C) 2010 Elsevier B V All rights reserved
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| 9. |
- García, Patricia, et al.
(author)
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Functional and genomic characterization of three novel cell lines derived from a metastatic gallbladder cancer tumor
- 2020
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In: Biological Research. - : Springer Science and Business Media LLC. - 0716-9760 .- 0717-6287. ; 53
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Journal article (peer-reviewed)abstract
- © 2020 The Author(s). Background: Gallbladder cancer (GBC) is the most common tumor of the biliary tract. The incidence of GBC shows a large geographic variability, being particularly frequent in Native American populations. In Chile, GBC represents the second cause of cancer-related death among women. We describe here the establishment of three novel cell lines derived from the ascitic fluid of a Chilean GBC patient, who presented 46% European, 36% Mapuche, 12% Aymara and 6% African ancestry. Results: After immunocytochemical staining of the primary cell culture, we isolated and comprehensively characterized three independent clones (PUC-GBC1, PUC-GBC2 and PUC-GBC3) by short tandem repeat DNA profiling and RNA sequencing as well as karyotype, doubling time, chemosensitivity, in vitro migration capability and in vivo tumorigenicity assay. Primary culture cells showed high expression of CK7, CK19, CA 19-9, MUC1 and MUC16, and negative expression of mesothelial markers. The three isolated clones displayed an epithelial phenotype and an abnormal structure and number of chromosomes. RNA sequencing confirmed the increased expression of cytokeratin and mucin genes, and also of TP53 and ERBB2 with some differences among the three cells lines, and revealed a novel exonic mutation in NF1. The PUC-GBC3 clone was the most aggressive according to histopathological features and the tumorigenic capacity in NSG mice. Conclusions: The first cell lines established from a Chilean GBC patient represent a new model for studying GBC in patients of Native American descent.
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