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Article ; Online: Detection of germline variants with pathogenic potential in 48 patients with familial colorectal cancer by using whole exome sequencing.

Singh, Ashish Kumar / Talseth-Palmer, Bente / Xavier, Alexandre / Scott, Rodney J / Drabløs, Finn / Sjursen, Wenche

2023 Volume 16, Issue 1, Page(s) 126

Abstract: Background: Hereditary genetic mutations causing predisposition to colorectal cancer are accountable for approximately 30% of all colorectal cancer cases. However, only a small fraction of these are high penetrant mutations occurring in DNA mismatch ... ...

Abstract	Background: Hereditary genetic mutations causing predisposition to colorectal cancer are accountable for approximately 30% of all colorectal cancer cases. However, only a small fraction of these are high penetrant mutations occurring in DNA mismatch repair genes, causing one of several types of familial colorectal cancer (CRC) syndromes. Most of the mutations are low-penetrant variants, contributing to an increased risk of familial colorectal cancer, and they are often found in additional genes and pathways not previously associated with CRC. The aim of this study was to identify such variants, both high-penetrant and low-penetrant ones. Methods: We performed whole exome sequencing on constitutional DNA extracted from blood of 48 patients suspected of familial colorectal cancer and used multiple in silico prediction tools and available literature-based evidence to detect and investigate genetic variants. Results: We identified several causative and some potentially causative germline variants in genes known for their association with colorectal cancer. In addition, we identified several variants in genes not typically included in relevant gene panels for colorectal cancer, including CFTR, PABPC1 and TYRO3, which may be associated with an increased risk for cancer. Conclusions: Identification of variants in additional genes that potentially can be associated with familial colorectal cancer indicates a larger genetic spectrum of this disease, not limited only to mismatch repair genes. Usage of multiple in silico tools based on different methods and combined through a consensus approach increases the sensitivity of predictions and narrows down a large list of variants to the ones that are most likely to be significant.
MeSH term(s)	Humans ; Colorectal Neoplasms, Hereditary Nonpolyposis/diagnosis ; Colorectal Neoplasms, Hereditary Nonpolyposis/genetics ; Exome Sequencing ; Genetic Predisposition to Disease ; Pedigree ; Germ-Line Mutation ; Germ Cells ; Colorectal Neoplasms/genetics ; Colorectal Neoplasms/diagnosis
Language	English
Publishing date	2023-06-09
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2411865-5
ISSN	1755-8794 ; 1755-8794
ISSN (online)	1755-8794
ISSN	1755-8794
DOI	10.1186/s12920-023-01562-3
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: The Prognostic Value of Methylation Signatures and

Meta, Rahmina / Boldt, Henning B / Kristensen, Bjarne W / Sahm, Felix / Sjursen, Wenche / Torp, Sverre H

Cancers

2021 Volume 13, Issue 6

Abstract: ... ...

Abstract	Background
Language	English
Publishing date	2021-03-12
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers13061262
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Article ; Online: Publisher Correction: A 39 kb structural variant causing Lynch syndrome detected by optical genome mapping and nanopore sequencing.

Bjørnstad, Pål Marius / Aaløkken, Ragnhild / Åsheim, June / Sundaram, Arvind Y M / Felde, Caroline N / Østby, G Henriette / Dalland, Marianne / Sjursen, Wenche / Carrizosa, Christian / Vigeland, Magnus D / Sorte, Hanne S / Sheng, Ying / Ariansen, Sarah L / Grindedal, Eli Marie / Gilfillan, Gregor D

European journal of human genetics : EJHG

2024 Volume 32, Issue 5, Page(s) 601–602

Language	English
Publishing date	2024-01-02
Publishing country	England
Document type	Published Erratum
ZDB-ID	1141470-4
ISSN	1476-5438 ; 1018-4813
ISSN (online)	1476-5438
ISSN	1018-4813
DOI	10.1038/s41431-023-01519-1
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Article ; Online: Detection of germline variants with pathogenic potential in 48 patients with familial colorectal cancer by using whole exome sequencing

Ashish Kumar Singh / Bente Talseth-Palmer / Alexandre Xavier / Rodney J. Scott / Finn Drabløs / Wenche Sjursen

BMC Medical Genomics, Vol 16, Iss 1, Pp 1-

2023 Volume 13

Abstract: Abstract Background Hereditary genetic mutations causing predisposition to colorectal cancer are accountable for approximately 30% of all colorectal cancer cases. However, only a small fraction of these are high penetrant mutations occurring in DNA ... ...

Abstract	Abstract Background Hereditary genetic mutations causing predisposition to colorectal cancer are accountable for approximately 30% of all colorectal cancer cases. However, only a small fraction of these are high penetrant mutations occurring in DNA mismatch repair genes, causing one of several types of familial colorectal cancer (CRC) syndromes. Most of the mutations are low-penetrant variants, contributing to an increased risk of familial colorectal cancer, and they are often found in additional genes and pathways not previously associated with CRC. The aim of this study was to identify such variants, both high-penetrant and low-penetrant ones. Methods We performed whole exome sequencing on constitutional DNA extracted from blood of 48 patients suspected of familial colorectal cancer and used multiple in silico prediction tools and available literature-based evidence to detect and investigate genetic variants. Results We identified several causative and some potentially causative germline variants in genes known for their association with colorectal cancer. In addition, we identified several variants in genes not typically included in relevant gene panels for colorectal cancer, including CFTR, PABPC1 and TYRO3, which may be associated with an increased risk for cancer. Conclusions Identification of variants in additional genes that potentially can be associated with familial colorectal cancer indicates a larger genetic spectrum of this disease, not limited only to mismatch repair genes. Usage of multiple in silico tools based on different methods and combined through a consensus approach increases the sensitivity of predictions and narrows down a large list of variants to the ones that are most likely to be significant.
Keywords	Whole exome sequencing (WES) ; Colorectal cancer (CRC) ; Lynch syndrome (LS) ; Familial colorectal cancer Type X (FCCTX) ; Mismatch repair (MMR) ; Copy number variation (CNV) ; Internal medicine ; RC31-1245 ; Genetics ; QH426-470
Subject code	616 ; 610
Language	English
Publishing date	2023-06-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
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Article ; Online: Functional Analyses of Rare Germline Missense

Hovland, Henrikke Nilsen / Mchaina, Eunice Kabanyana / Høberg-Vetti, Hildegunn / Ariansen, Sarah Louise / Sjursen, Wenche / Van Ghelue, Marijke / Haukanes, Bjørn Ivar / Knappskog, Per Morten / Aukrust, Ingvild / Ognedal, Elisabet

Genes

2023 Volume 14, Issue 2

Abstract: The BRCA1 protein is implicated in numerous important cellular processes to prevent genomic instability and tumorigenesis, and pathogenic germline variants predispose carriers to hereditary breast and ovarian cancer (HBOC). Most functional studies of ... ...

Abstract	The BRCA1 protein is implicated in numerous important cellular processes to prevent genomic instability and tumorigenesis, and pathogenic germline variants predispose carriers to hereditary breast and ovarian cancer (HBOC). Most functional studies of missense variants in
MeSH term(s)	Female ; Humans ; BRCA1 Protein/genetics ; Germ Cells/metabolism ; Mutation, Missense ; Ovarian Neoplasms/genetics ; Protein Domains ; Breast Neoplasms/genetics
Chemical Substances	BRCA1 Protein ; BRCA1 protein, human
Language	English
Publishing date	2023-01-19
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2527218-4
ISSN	2073-4425 ; 2073-4425
ISSN (online)	2073-4425
ISSN	2073-4425
DOI	10.3390/genes14020262
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Article ; Online: Detecting copy number variation in next generation sequencing data from diagnostic gene panels.

Singh, Ashish Kumar / Olsen, Maren Fridtjofsen / Lavik, Liss Anne Solberg / Vold, Trine / Drabløs, Finn / Sjursen, Wenche

BMC medical genomics

2021 Volume 14, Issue 1, Page(s) 214

Abstract: Background: Detection of copy number variation (CNV) in genes associated with disease is important in genetic diagnostics, and next generation sequencing (NGS) technology provides data that can be used for CNV detection. However, CNV detection based on ... ...

Abstract	Background: Detection of copy number variation (CNV) in genes associated with disease is important in genetic diagnostics, and next generation sequencing (NGS) technology provides data that can be used for CNV detection. However, CNV detection based on NGS data is in general not often used in diagnostic labs as the data analysis is challenging, especially with data from targeted gene panels. Wet lab methods like MLPA (MRC Holland) are widely used, but are expensive, time consuming and have gene-specific limitations. Our aim has been to develop a bioinformatic tool for CNV detection from NGS data in medical genetic diagnostic samples. Results: Our computational pipeline for detection of CNVs in NGS data from targeted gene panels utilizes coverage depth of the captured regions and calculates a copy number ratio score for each region. This is computed by comparing the mean coverage of the sample with the mean coverage of the same region in other samples, defined as a pool. The pipeline selects pools for comparison dynamically from previously sequenced samples, using the pool with an average coverage depth that is nearest to the one of the samples. A sliding window-based approach is used to analyze each region, where length of sliding window and sliding distance can be chosen dynamically to increase or decrease the resolution. This helps in detecting CNVs in small or partial exons. With this pipeline we have correctly identified the CNVs in 36 positive control samples, with sensitivity of 100% and specificity of 91%. We have detected whole gene level deletion/duplication, single/multi exonic level deletion/duplication, partial exonic deletion and mosaic deletion. Since its implementation in mid-2018 it has proven its diagnostic value with more than 45 CNV findings in routine tests. Conclusions: With this pipeline as part of our diagnostic practices it is now possible to detect partial, single or multi-exonic, and intragenic CNVs in all genes in our target panel. This has helped our diagnostic lab to expand the portfolio of genes where we offer CNV detection, which previously was limited by the availability of MLPA kits.
MeSH term(s)	DNA Copy Number Variations
Language	English
Publishing date	2021-08-31
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1755-8794
ISSN (online)	1755-8794
DOI	10.1186/s12920-021-01059-x
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Article ; Online: sMETASeq: Combined Profiling of Microbiota and Host Small RNAs.

Mjelle, Robin / Aass, Kristin Roseth / Sjursen, Wenche / Hofsli, Eva / Sætrom, Pål

iScience

2020 Volume 23, Issue 5, Page(s) 101131

Abstract: Understanding microbial communities' roles in human health and disease requires methods that accurately characterize the microbial composition and their activity and effects within human biological samples. We present sMETASeq (small RNA Metagenomics by ... ...

Abstract	Understanding microbial communities' roles in human health and disease requires methods that accurately characterize the microbial composition and their activity and effects within human biological samples. We present sMETASeq (small RNA Metagenomics by Sequencing), a novel method that uses sequencing of small RNAs to jointly measure host small RNA expression and create metagenomic profiles and detect small bacterial RNAs. We evaluated the performance of sMETASeq on a mock bacterial community and demonstrated its use on different human samples, including colon cancer, oral leukoplakia, cervix cancer, and a panel of human biofluids. In all datasets, the detected microbes reflected the biology of the different sample types.
Language	English
Publishing date	2020-05-04
Publishing country	United States
Document type	Journal Article
ISSN	2589-0042
ISSN (online)	2589-0042
DOI	10.1016/j.isci.2020.101131
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Article ; Online: Characterization of POLE c.1373A > T p.(Tyr458Phe), causing high cancer risk.

Rocque, Mariève J / Leipart, Vilde / Kumar Singh, Ashish / Mur, Pilar / Olsen, Maren F / Engebretsen, Lars F / Martin-Ramos, Edgar / Aligué, Rosa / Sætrom, Pål / Valle, Laura / Drabløs, Finn / Otterlei, Marit / Sjursen, Wenche

Molecular genetics and genomics : MGG

2023 Volume 298, Issue 3, Page(s) 555–566

Abstract: The cancer syndrome polymerase proofreading-associated polyposis results from germline mutations in the POLE and POLD1 genes. Mutations in the exonuclease domain of these genes are associated with hyper- and ultra-mutated tumors with a predominance of ... ...

Abstract	The cancer syndrome polymerase proofreading-associated polyposis results from germline mutations in the POLE and POLD1 genes. Mutations in the exonuclease domain of these genes are associated with hyper- and ultra-mutated tumors with a predominance of base substitutions resulting from faulty proofreading during DNA replication. When a new variant is identified by gene testing of POLE and POLD1, it is important to verify whether the variant is associated with PPAP or not, to guide genetic counseling of mutation carriers. In 2015, we reported the likely pathogenic (class 4) germline POLE c.1373A > T p.(Tyr458Phe) variant and we have now characterized this variant to verify that it is a class 5 pathogenic variant. For this purpose, we investigated (1) mutator phenotype in tumors from two carriers, (2) mutation frequency in cell-based mutagenesis assays, and (3) structural consequences based on protein modeling. Whole-exome sequencing of two tumors identified an ultra-mutator phenotype with a predominance of base substitutions, the majority of which are C > T. A SupF mutagenesis assay revealed increased mutation frequency in cells overexpressing the variant of interest as well as in isogenic cells encoding the variant. Moreover, exonuclease repair yeast-based assay supported defect in proofreading activity. Lastly, we present a homology model of human POLE to demonstrate structural consequences leading to pathogenic impact of the p.(Tyr458Phe) mutation. The three lines of evidence, taken together with updated co-segregation and previously published data, allow the germline variant POLE c.1373A > T p.(Tyr458Phe) to be reclassified as a class 5 variant. That means the variant is associated with PPAP.
MeSH term(s)	Humans ; DNA Polymerase II/genetics ; DNA Polymerase II/chemistry ; DNA Polymerase II/metabolism ; Poly-ADP-Ribose Binding Proteins/genetics ; Neoplasms/genetics ; Mutation ; Exonucleases/genetics ; Exonucleases/metabolism
Chemical Substances	N-(3-phenyl-n-propyl)-1-phenyl-2-aminopropane (131903-56-5) ; DNA Polymerase II (EC 2.7.7.7) ; Poly-ADP-Ribose Binding Proteins ; Exonucleases (EC 3.1.-)
Language	English
Publishing date	2023-03-01
Publishing country	Germany
Document type	Journal Article
ZDB-ID	2044817-X
ISSN	1617-4623 ; 1617-4615
ISSN (online)	1617-4623
ISSN	1617-4615
DOI	10.1007/s00438-023-02000-w
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Article ; Online: Small RNA expression from viruses, bacteria and human miRNAs in colon cancer tissue and its association with microsatellite instability and tumor location.

Mjelle, Robin / Sjursen, Wenche / Thommesen, Liv / Sætrom, Pål / Hofsli, Eva

BMC cancer

2019 Volume 19, Issue 1, Page(s) 161

Abstract: Background: MicroRNAs (miRNA) and other small RNAs are frequently dysregulated in cancer and are promising biomarkers for colon cancer. Here we profile human, virus and bacteria small RNAs in normal and tumor tissue from early stage colon cancer and ... ...

Abstract	Background: MicroRNAs (miRNA) and other small RNAs are frequently dysregulated in cancer and are promising biomarkers for colon cancer. Here we profile human, virus and bacteria small RNAs in normal and tumor tissue from early stage colon cancer and correlate the expression with clinical parameters. Methods: Small RNAs from colon cancer tissue and adjacent normal mucosa of 48 patients were sequenced using Illumina high-throughput sequencing. Clinical parameters were correlated with the small RNA expression data using linear models. We performed a meta-analysis by comparing publicly available small RNA sequencing datasets with our original sequencing data to confirm the main findings. Results: We identified 331 differentially expressed miRNAs between tumor and normal samples. We found that the major changes in miRNA expression between left and right colon are due to miRNAs located within the Hox-developmental genes, including miR-10b, miR-196b and miR-615. Further, we identified new miRNAs associated with microsatellite instability (MSI), including miR-335, miR-26 and miR-625. We performed a meta-analysis on all publicly available miRNA-seq datasets and identified 117 common miRNAs that were differentially expressed between tumor and normal tissue. The miRNAs miR-135b and miR-31 were the most significant upregulated miRNA in tumor across all datasets. The miRNA miR-133a was the most strongly downregulated miRNA in our dataset and also showed consistent downregulation in the other datasets. The miRNAs associated with MSI and tumor location in our data showed similar changes in the other datasets. Finally, we show that small RNAs from Epstein-Barr virus and Fusobacterium nucleatum are differentially expressed between tumor and normal adjacent tissue. Conclusions: Small RNA profiling in colon cancer tissue revealed novel RNAs associated with MSI and tumor location. We show that Fusobacterium nucleatum are detectable at the RNA-level in colon tissue, and that both Fusobacterium nucleatum and Epstein-Barr virus separate tumor and normal tissue.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Biomarkers, Tumor ; Cohort Studies ; Colonic Neoplasms/genetics ; Colonic Neoplasms/microbiology ; Databases, Genetic ; Female ; Fusobacterium nucleatum/genetics ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Herpesvirus 4, Human/genetics ; High-Throughput Nucleotide Sequencing ; Humans ; Male ; MicroRNAs/genetics ; Microsatellite Instability ; Middle Aged ; RNA, Bacterial/genetics ; RNA, Viral/genetics ; Retrospective Studies
Chemical Substances	Biomarkers, Tumor ; MIRN155 microRNA, human ; MicroRNAs ; RNA, Bacterial ; RNA, Viral
Language	English
Publishing date	2019-02-20
Publishing country	England
Document type	Comparative Study ; Journal Article ; Meta-Analysis
ISSN	1471-2407
ISSN (online)	1471-2407
DOI	10.1186/s12885-019-5330-0
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Article ; Online: sMETASeq

Robin Mjelle / Kristin Roseth Aass / Wenche Sjursen / Eva Hofsli / Pål Sætrom

iScience, Vol 23, Iss 5, Pp - (2020)

Combined Profiling of Microbiota and Host Small RNAs

2020

Abstract: Summary: Understanding microbial communities' roles in human health and disease requires methods that accurately characterize the microbial composition and their activity and effects within human biological samples. We present sMETASeq (small RNA ... ...

Abstract	Summary: Understanding microbial communities' roles in human health and disease requires methods that accurately characterize the microbial composition and their activity and effects within human biological samples. We present sMETASeq (small RNA Metagenomics by Sequencing), a novel method that uses sequencing of small RNAs to jointly measure host small RNA expression and create metagenomic profiles and detect small bacterial RNAs. We evaluated the performance of sMETASeq on a mock bacterial community and demonstrated its use on different human samples, including colon cancer, oral leukoplakia, cervix cancer, and a panel of human biofluids. In all datasets, the detected microbes reflected the biology of the different sample types.
Keywords	Genomics ; Microbiology ; Bioinformatics ; Science ; Q
Language	English
Publishing date	2020-05-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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