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Search Results: 1 - 10 of 89660 matches for " Rolf I Skotheim "
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Transcriptome instability in colorectal cancer identified by exon microarray analyses: Associations with splicing factor expression levels and patient survival
Anita Sveen, Trude H ?gesen, Arild Nesbakken, Torleiv O Rognum, Ragnhild A Lothe, Rolf I Skotheim
Genome Medicine , 2011, DOI: 10.1186/gm248
Abstract: Exon microarray profiles from two independent series including a total of 160 CRCs were investigated for their relative amounts of exon usage differences. Each exon in each sample was assigned an alternative splicing score calculated by the FIRMA algorithm. Amounts of deviating exon usage per sample were derived from exons with extreme splicing scores.There was great heterogeneity within both series in terms of sample-wise amounts of deviating exon usage. This was strongly associated with the expression levels of approximately half of 280 splicing factors (54% and 48% of splicing factors were significantly correlated to deviating exon usage amounts in the two series). Samples with high or low amounts of deviating exon usage, associated with overall transcriptome instability, were almost completely separated into their respective groups by hierarchical clustering analysis of splicing factor expression levels in both sample series. Samples showing a preferential tendency towards deviating exon skipping or inclusion were associated with skewed transcriptome instability. There were significant associations between transcriptome instability and reduced patient survival in both sample series. In the test series, patients with skewed transcriptome instability showed the strongest prognostic association (P = 0.001), while a combination of the two characteristics showed the strongest association with poor survival in the validation series (P = 0.03).We have described transcriptome instability as a characteristic of CRC. This transcriptome instability has associations with splicing factor expression levels and poor patient survival.Colorectal cancer (CRC) is a prevalent disease with a world-wide incidence of more than one million new cases each year, making it the third most commonly diagnosed cancer among men and women [1]. Colorectal tumors are heterogeneous and evolve through multiple pathways. Malignant transformation is dependent on the accumulation of numerous genetic c
High Frequency of Fusion Transcripts Involving TCF7L2 in Colorectal Cancer: Novel Fusion Partner and Splice Variants
Torfinn Nome, Andreas M. Hoff, Anne Cathrine Bakken, Torleiv O. Rognum, Arild Nesbakken, Rolf I. Skotheim
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0091264
Abstract: VTI1A-TCF7L2 was reported as a recurrent fusion gene in colorectal cancer (CRC), found to be expressed in three out of 97 primary cancers, and one cell line, NCI-H508, where a genomic deletion joins the two genes [1]. To investigate this fusion further, we analyzed high-throughput DNA and RNA sequencing data from seven CRC cell lines, and identified the gene RP11-57H14.3 (ENSG00000225292) as a novel fusion partner for TCF7L2. The fusion was discovered from both genome and transcriptome data in the HCT116 cell line. By triplicate nested RT-PCR, we tested both the novel fusion transcript and VTI1A-TCF7L2 for expression in a series of 106 CRC tissues, 21 CRC cell lines, 14 normal colonic mucosa, and 20 normal tissues from miscellaneous anatomical sites. Altogether, 42% and 45% of the CRC samples expressed VTI1A-TCF7L2 and TCF7L2-RP11-57H14.3 fusion transcripts, respectively. The fusion transcripts were both seen in 29% of the normal colonic mucosa samples, and in 25% and 75% of the tested normal tissues from other organs, revealing that the TCF7L2 fusion transcripts are neither specific to cancer nor to the colon and rectum. Seven different splice variants were detected for the VTI1A-TCF7L2 fusion, of which three are novel. Four different splice variants were detected for the TCF7L2-RP11-57H14.3 fusion. In conclusion, we have identified novel variants of VTI1A-TCF7L2 fusion transcripts, including a novel fusion partner gene, RP11-57H14.3, and demonstrated detectable levels in a large fraction of CRC samples, as well as in normal colonic mucosa and other tissue types. We suggest that the fusion transcripts observed in a high frequency of samples are transcription induced chimeras that are expressed at low levels in most samples. The similar fusion transcripts induced by genomic rearrangements observed in individual cancer cell lines may yet have oncogenic potential as suggested in the original study by Bass et al.
A Tumor-Associated Mutation of FYVE-CENT Prevents Its Interaction with Beclin 1 and Interferes with Cytokinesis
Antonia P. Sagona,Ioannis P. Nezis,Kristi G. Bache,Kaisa Haglund,Anne Cathrine Bakken,Rolf I. Skotheim,Harald Stenmark
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0017086
Abstract: The tumor suppressor activity of Beclin 1 (BECN1), a subunit of class III phosphatidylinositol 3-kinase complex, has been attributed to its regulation of apoptosis and autophagy. Here, we identify FYVE-CENT (ZFYVE26), a phosphatidylinositol 3-phosphate binding protein important for cytokinesis, as a novel interacting protein of Beclin 1. A mutation in FYVE-CENT (R1945Q) associated with breast cancer abolished the interaction between FYVE-CENT and Beclin 1, and reduced the localization of these proteins at the intercellular bridge during cytokinesis. Breast cancer cells containing the FYVE-CENT R1945Q mutation displayed a significant increase in cytokinetic profiles and bi - multinuclear phenotype. Both Beclin 1 and FYVE-CENT were found to be downregulated in advanced breast cancers. These findings suggest a positive feedback loop for recruitment of FYVE-CENT and Beclin 1 to the intercellular bridge during cytokinesis, and reveal a novel potential tumor suppressor mechanism for Beclin 1.
Assessment of Fusion Gene Status in Sarcomas Using a Custom Made Fusion Gene Microarray
Marthe L?vf, Gard O. S. Thomassen, Fredrik Mertens, Nuno Cerveira, Manuel R. Teixeira, Ragnhild A. Lothe, Rolf I. Skotheim
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0070649
Abstract: Sarcomas are relatively rare malignancies and include a large number of histological subgroups. Based on morphology alone, the differential diagnoses of sarcoma subtypes can be challenging, but the identification of specific fusion genes aids correct diagnostication. The presence of individual fusion products are routinely investigated in Pathology labs. However, the methods used are time-consuming and based on prior knowledge about the expected fusion gene and often the most likely break-point. In this study, 16 sarcoma samples, representing seven different sarcoma subtypes with known fusion gene status from a diagnostic setting, were investigated using a fusion gene microarray. The microarray was designed to detect all possible exon-exon breakpoints between all known fusion genes in a single analysis. An automated scoring of the microarray data from the 38 known sarcoma-related fusion genes identified the correct fusion gene among the top-three hits in 11 of the samples. The analytical sensitivity may be further optimised, but we conclude that a sarcoma-fusion gene microarray is suitable as a time-saving screening tool to identify the majority of the correct fusion genes.
Phospholipase C Isozymes Are Deregulated in Colorectal Cancer – Insights Gained from Gene Set Enrichment Analysis of the Transcriptome
Stine A. Danielsen, Lina Cekaite, Trude H. ?gesen, Anita Sveen, Arild Nesbakken, Espen Thiis-Evensen, Rolf I. Skotheim, Guro E. Lind, Ragnhild A. Lothe
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0024419
Abstract: Colorectal cancer (CRC) is one of the most common cancer types in developed countries. To identify molecular networks and biological processes that are deregulated in CRC compared to normal colonic mucosa, we applied Gene Set Enrichment Analysis to two independent transcriptome datasets, including a total of 137 CRC and ten normal colonic mucosa samples. Eighty-two gene sets as described by the Kyoto Encyclopedia of Genes and Genomes database had significantly altered gene expression in both datasets. These included networks associated with cell division, DNA maintenance, and metabolism. Among signaling pathways with known changes in key genes, the “Phosphatidylinositol signaling network”, comprising part of the PI3K pathway, was found deregulated. The downregulated genes in this pathway included several members of the Phospholipase C protein family, and the reduced expression of two of these, PLCD1 and PLCE1, were successfully validated in CRC biopsies (n = 70) and cell lines (n = 19) by quantitative analyses. The repression of both genes was found associated with KRAS mutations (P = 0.005 and 0.006, respectively), and we observed that microsatellite stable carcinomas with reduced PLCD1 expression more frequently had TP53 mutations (P = 0.002). Promoter methylation analyses of PLCD1 and PLCE1 performed in cell lines and tumor biopsies revealed that methylation of PLCD1 can contribute to reduced expression in 40% of the microsatellite instable carcinomas. In conclusion, we have identified significantly deregulated pathways in CRC, and validated repression of PLCD1 and PLCE1 expression. This illustrates that the GSEA approach may guide discovery of novel biomarkers in cancer.
The loss of NKX3.1 expression in testicular – and prostate – cancers is not caused by promoter hypermethylation
Guro E Lind, Rolf I Skotheim, Mario F Fraga, Vera M Abeler, Rui Henrique, Fahri Saatcioglu, Manel Esteller, Manuel R Teixeira, Ragnhild A Lothe
Molecular Cancer , 2005, DOI: 10.1186/1476-4598-4-8
Abstract: Down-regulation of NKX3.1 expression was generally not caused by promoter hypermethylation, which was only found in one TGCT. However, other epigenetic mechanisms, such as modulation of chromatin structure or modifications of histones, may explain the lack of NKX3.1 expression, which is seen in most TGCTs and prostate cancer specimens.The protein expression of the homeobox gene NK3 transcription factor related locus 1 (NKX3.1) is highly specific for the prostate and the testis [1-3], and is frequently lost in cancers of these two tissue types [1,4,5]. NKX3.1 is located in chromosome band 8p21 [2,6,7], a region that undergoes frequent allelic imbalance in prostatic intraepithelial neoplasia (PIN) and prostate carcinomas [8,9]. In mice, targeted disruption of Nkx3.1 leads to prostatic epithelial hyperplasia and dysplasia [10,11], and over-expression of exogenous NKX3.1 suppresses growth and tumorigenicity in human prostate carcinoma cell lines [12]. However, the expression levels and possible role for NKX3.1 during prostate cancer progression in humans is still being debated [13-15]. No gene mutations of NKX3.1 have been found [6], and NXK3.1 is therefore believed to be epigenetically inactivated in the cases with loss of protein expression [1,5,16]. Only one study has reported NKX3.1 protein expression in testicular germ cell tumors (TGCTs), however the series analyzed was large, including a total of more than 500 samples, and NKX3.1 was found absent in all embryonal carcinomas and present in only 15–20% of the seminomas as well as among the differentiated histological subtypes of germ cell tumors [5].During the last decade, epigenetic changes in cancer have been frequently reported and are now recognized to be at least as common as genetic changes [17]. The best characterized epigenetic mechanism is DNA hypermethylation, in which cytosines located within selected CpG sites in the gene promoters become methylated, thereby inactivating gene expression. Several tumor s
Hypermethylated MAL gene – a silent marker of early colon tumorigenesis
Guro E Lind, Terje Ahlquist, Matthias Kolberg, Marianne Berg, Mette Ekn?s, Miguel A Alonso, Anne Kallioniemi, Gunn I Meling, Rolf I Skotheim, Torleiv O Rognum, Espen Thiis-Evensen, Ragnhild A Lothe
Journal of Translational Medicine , 2008, DOI: 10.1186/1479-5876-6-13
Abstract: Using methylation-specific polymerase chain reaction (MSP) the promoter methylation status of MAL was analyzed in 218 samples, including normal mucosa (n = 44), colorectal adenomas (n = 63), carcinomas (n = 65), and various cancer cell lines (n = 46). Direct bisulphite sequencing was performed to confirm the MSP results. MAL gene expression was investigated with real time quantitative analyses before and after epigenetic drug treatment. Immunohistochemical analysis of MAL was done using normal colon mucosa samples (n = 5) and a tissue microarray with 292 colorectal tumors.Bisulphite sequencing revealed that the methylation was unequally distributed within the MAL promoter and by MSP analysis a region close to the transcription start point was shown to be hypermethylated in the majority of colorectal carcinomas (49/61, 80%) as well as in adenomas (45/63, 71%). In contrast, only a minority of the normal mucosa samples displayed hypermethylation (1/23, 4%). The hypermethylation of MAL was significantly associated with reduced or lost gene expression in in vitro models. Furthermore, removal of the methylation re-induced gene expression in colon cancer cell lines. Finally, MAL protein was expressed in epithelial cells of normal colon mucosa, but not in the malignant cells of the same type.Promoter hypermethylation of MAL was present in the vast majority of benign and malignant colorectal tumors, and only rarely in normal mucosa, which makes it suitable as a diagnostic marker for early colorectal tumorigenesis.Epigenetic changes – non-sequence-based alterations that are inherited through cell division [1] – are frequently seen in human cancers, and likewise as genetic alterations they may lead to disruption of gene function. In colorectal cancer, several tumour suppressor genes have been identified to be epigenetically inactivated by CpG island promoter hypermethylation, including the DNA mismatch repair gene MLH1 [2-4], the gatekeeper APC [5], and the cell cycle inhibito
Identification of an epigenetic biomarker panel with high sensitivity and specificity for colorectal cancer and adenomas
Guro E Lind, Stine A Danielsen, Terje Ahlquist, Marianne A Merok, Kim Andresen, Rolf I Skotheim, Merete Hektoen, Torleiv O Rognum, Gunn I Meling, Geir Hoff, Michael Bretthauer, Espen Thiis-Evensen, Arild Nesbakken, Ragnhild A Lothe
Molecular Cancer , 2011, DOI: 10.1186/1476-4598-10-85
Abstract: Candidate biomarkers were subjected to quantitative methylation analysis in test sets of tissue samples from colorectal cancers, adenomas, and normal colonic mucosa. All findings were verified in independent clinical validation series. A total of 523 human samples were included in the study. Receiver operating characteristic (ROC) curve analysis was used to evaluate the performance of the biomarker panel.Promoter hypermethylation of the genes CNRIP1, FBN1, INA, MAL, SNCA, and SPG20 was frequent in both colorectal cancers (65-94%) and adenomas (35-91%), whereas normal mucosa samples were rarely (0-5%) methylated. The combined sensitivity of at least two positives among the six markers was 94% for colorectal cancers and 93% for adenoma samples, with a specificity of 98%. The resulting areas under the ROC curve were 0.984 for cancers and 0.968 for adenomas versus normal mucosa.The novel epigenetic marker panel shows very high sensitivity and specificity for both colorectal cancers and adenomas. Our findings suggest this biomarker panel to be highly suitable for early tumor detection.Colorectal cancer is the third most common cancer type in the US and is a major contributor to cancer-death [1]. Most cases of colorectal cancer develop from benign precursors (adenomas) during a long time interval. This provides a good opportunity for detection of colorectal cancer at an early curable stage and to screen for potentially pre-malignant adenomas [2]. Both flexible sigmoidoscopy and the Fecal Occult Blood Test (FOBT) have been tested in randomized trials and shown to reduce mortality from colorectal cancer [3]. By sigmoidoscopy adenomas may be detected and removed and thus the incidence of cancer will be reduced [4], however, this screening is invasive and cumbersome for the patient. FOBT on the other hand is non-invasive and currently the most commonly used screening test for colorectal cancer in Europe. Although the sensitivity and specificity measurements of FOBT have been
Gene methylation profiles of normal mucosa, and benign and malignant colorectal tumors identify early onset markers
Terje Ahlquist, Guro E Lind, Vera L Costa, Gunn I Meling, Morten Vatn, Geir S Hoff, Torleiv O Rognum, Rolf I Skotheim, Espen Thiis-Evensen, Ragnhild A Lothe
Molecular Cancer , 2008, DOI: 10.1186/1476-4598-7-94
Abstract: The methylation status of eleven genes (ADAMTS1, CDKN2A, CRABP1, HOXA9, MAL, MGMT, MLH1, NR3C1, PTEN, RUNX3, and SCGB3A1) was determined in 154 tissue samples including normal mucosa, adenomas, and carcinomas of the colorectum. The gene-specific and widespread methylation status among the carcinomas was related to patient gender and age, and microsatellite instability status. Possible CIMP tumors were identified by comparing the methylation profile with microsatellite instability (MSI), BRAF-, KRAS-, and TP53 mutation status.The mean number of methylated genes per sample was 0.4 in normal colon mucosa from tumor-free individuals, 1.2 in mucosa from cancerous bowels, 2.2 in adenomas, and 3.9 in carcinomas. Widespread methylation was found in both adenomas and carcinomas. The promoters of ADAMTS1, MAL, and MGMT were frequently methylated in benign samples as well as in malignant tumors, independent of microsatellite instability. In contrast, normal mucosa samples taken from bowels without tumor were rarely methylated for the same genes. Hypermethylated CRABP1, MLH1, NR3C1, RUNX3, and SCGB3A1 were shown to be identifiers of carcinomas with microsatellite instability. In agreement with the CIMP concept, MSI and mutated BRAF were associated with samples harboring hypermethylation of several target genes.Methylated ADAMTS1, MGMT, and MAL are suitable as markers for early tumor detection.Most cases of colorectal cancer (CRC) originate from adenomas. The malignant potential of adenomas increases with size, grade of dysplasia, and degree of villous components,[1] along with the number and order of genetic and epigenetic aberrations.[2] The majority (~85%) of the sporadic carcinomas are characterized by chromosomal aberrations, referred to as a chromosomal unstable (CIN) phenotype, whereas the smaller group (~15%) typically show microsatellite instability (MSI) caused by defect DNA mismatch repair.[2] Most CIN tumors are microsatellite stable (MSS). A third molecular phenotyp
Gene expression profiles of primary colorectal carcinomas, liver metastases, and carcinomatoses
Kristine Kleivi, Guro E Lind, Chieu B Diep, Gunn I Meling, Lin T Brandal, Jahn M Nesland, Ola Myklebost, Torleiv O Rognum, Karl-Erik Giercksky, Rolf I Skotheim, Ragnhild A Lothe
Molecular Cancer , 2007, DOI: 10.1186/1476-4598-6-2
Abstract: Transcriptome profiles of colorectal cancer metastases independent of tumor site, as well as separate profiles associated with primary carcinomas, liver metastases, or peritoneal carcinomatoses, were assessed by use of Bayesian statistics. Gains of chromosome arm 5p are common in peritoneal carcinomatoses and several candidate genes (including PTGER4, SKP2, and ZNF622) mapping to this region were overexpressed in the tumors. Expression signatures stratified on TP53 mutation status were identified across all tumors regardless of stage. Furthermore, the gene expression levels for the in vivo tumors were compared with an in vitro model consisting of cell lines representing all three tumor stages established from one patient.By statistical analysis of gene expression data from primary colorectal carcinomas, liver metastases, and carcinomatoses, we are able to identify genetic patterns associated with the different stages of tumorigenesis.Colorectal cancer (CRC) is the second most common cause of cancer related deaths in developed countries, including Norway [1,2]. Despite the fact that metastases are the leading cause of colorectal cancer deaths, the majority of genetic studies of colorectal carcinogenesis have focused on changes found in primary carcinomas, and the knowledge about the underlying molecular changes in more advanced disease stages remain limited. To obtain insights to this process, identification of molecular key events that distinguish primary from metastatic tumors is important. DNA microarray technology has become powerful for whole-genome investigations [3]. Recently, several reports have shown that results obtained by this technology can distinguish among subgroups of the same cancer tissue [4-7] as well as among different cancer types [8]. Additionally, genetic profiles have been identified that predict patients' clinical outcome in cancers of the breast, lung, central nervous system, digestive system, and prostate [9-15]. Several studies has invest
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