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Search Results: 1 - 10 of 461973 matches for " Ragnhild A Lothe "
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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
Association between long-term neuro-toxicities in testicular cancer survivors and polymorphisms in glutathione-s-transferase-P1 and -M1, a retrospective cross sectional study
Jan Oldenburg, Sigrid M Kraggerud, Marianne Bryd?y, Milada Cvancarova, Ragnhild A Lothe, Sophie D Fossa
Journal of Translational Medicine , 2007, DOI: 10.1186/1479-5876-5-70
Abstract: A total of 238 TCSs, who had received cisplatin-based chemotherapy at median twelve years earlier, had participated in a long-term follow-up survey which assessed the prevalence of self-reported paresthesias in fingers/toes, Raynaud-like phenomena in fingers/toes, tinnitus, and hearing impairment. From all TCSs lymphocyte-derived DNA was analyzed for the functional A→G polymorphism at bp 304 in GSTP1, and deletions in GST-M1 and GST-T1. Evaluation of associations between GST polymorphisms and self-reported toxicities included adjustment for prior treatment.All six evaluated toxicities were significantly associated with the cumulative dose of cisplatin and/or bleomycin. Compared to TCSs with either GSTP1-AG or GSTP1-AA, the 37 TCSs with the genotype GSTP1-GG, were significantly less bothered by paresthesias in fingers and toes (p = 0.039, OR 0.46 [0.22–0.96] and p = 0.023, OR 0.42 [0.20–0.88], respectively), and tinnitus (p = 0.008, OR 0.33 [0.14–0.74]). Furthermore, absence of functional GSTM1 protected against hearing impairment (p = 0.025, OR 1.81 [1.08–3.03]).In TCSs long-term self-reported chemotherapy-induced toxicities are associated with functional polymorphisms in GSTP1 and GSTM1. Hypothetically, absence of GST-M1 leaves more glutathione as substrate for the co-expressed GST-P1. Also intracellular inactivation of pro-apoptotic mediators represents a possible explanation of our findings. Genotyping of these GSTs might be a welcomed step towards a more individualized treatment of patients with metastatic testicular cancer.The progress of cisplatin-based chemotherapy has changed the once dark prospects of disseminated testicular cancer (TC) into a model of a curable neoplasm [1,2]. This success story of oncological treatment however, is shadowed by an increase in reports on long-term somatic and psychosocial sequalae in testicular cancer survivors (TCSs) [3,4]. Cisplatin (C) is the cornerstone of chemotherapeutic treatment of TC. It has usually been combined wi
Tumor Spreading to the Contralateral Ovary in Bilateral Ovarian Carcinoma Is a Late Event in Clonal Evolution
Francesca Micci,Lisbeth Haugom,Terje Ahlquist,Vera M. Abeler,Claes G. Trope,Ragnhild A. Lothe,Sverre Heim
Journal of Oncology , 2010, DOI: 10.1155/2010/646340
Abstract: Cancer of the ovary is bilateral in 25%. Cytogenetic analysis could determine whether the disease in bilateral cases is metastatic or two separately occurring primary tumors, but karyotypic information comparing the two cancerous ovaries is limited to a single report with 11 informative cases. We present a series of 32 bilateral ovarian carcinoma cases, analyzed by karyotyping and high-resolution CGH. Our karyotypic findings showed that spreading to the contralateral ovary had occurred in bilateral ovarian cancer cases and that it was a late event in the clonal evolution of the tumors. This was confirmed by the large number of similar changes detected by HR-CGH in the different lesions from the same patient. The chromosomal bands most frequently involved in structural rearrangements were 19p13 (n=12) and 19q13 (n=11). The chromosomal bands most frequently gained by both tumorous ovaries were 5p14 (70%), 8q23-24 (65%), 1q23-24 (57%), and 12p12 (48%), whereas the most frequently lost bands were 17p11 (78%), 17p13 (74%), 17p12 (70%), 22q13 (61%), 8p21 and 19q13 (52%), and 8p22-23 (48%). This is the first time that 5p14 is seen gained at such a high frequency in cancer of the ovary; possibly oncogene(s) involved in bilateral ovarian carcinogenesis or tumor progression may reside in this band.
MDM2 antagonist Nutlin-3a potentiates antitumour activity of cytotoxic drugs in sarcoma cell lines
Hege O Ohnstad, Erik B Paulsen, Paul Noordhuis, Marianne Berg, Ragnhild A Lothe, Lyubomir T Vassilev, Ola Myklebost
BMC Cancer , 2011, DOI: 10.1186/1471-2407-11-211
Abstract: A panel of sarcoma cell lines with different TP53 and MDM2 status were treated with Nutlin-3a combined with Doxorubicin, Methotrexate or Cisplatin, and their combination index determined.Clear synergism was observed when Doxorubicin and Nutlin-3a were combined in cell lines with wild-type TP53 and amplified MDM2, or with Methotrexate in both MDM2 normal and amplified sarcoma cell lines, allowing for up to tenfold reduction of cytotoxic drug dose. Interestingly, Nutlin-3a seemed to potentiate the effect of classical drugs as Doxorubicin and Cisplatin in cell lines with mutated TP53, but inhibited the effect of Methotrexate.The use of Nutlin in combination with classical sarcoma chemotherapy shows promising preclinical potential, but since clear biomarkers are still lacking, clinical trials should be followed up with detailed tumour profiling.The TP53 gene, coding for the transcription factor p53, is thought to be the most frequently mutated gene in cancer, inactivated in about 50% of all tumours. However, aberrations of this pathway are probably even more wide-spread, as tumours retaining wild-type p53 (TP53Wt) might have defects in other parts of the pathway [1]. In sarcomas, malignant tumours resembling mesenchymal tissue, amplification of MDM2 (murine double minute 2) is relatively common (20%) in tumours having TP53Wt, resulting in disabled p53 function because overexpressed MDM2 protein binds to and inactivates p53 [2,3]. Remaining tumours may have other aberrations in their p53 pathway, either p53 mutations (TP53Mut, 11-31% depending on subtype), or other changes in the downstream pathway that do not affect the level of MDM2 (MDM2Wt/TP53Wt, 11-88% depending on subtype) [4-6].Sarcomas are among the more frequent cancers among children [7], and both children and adults are treated with intensive surgery, chemotherapy or radiation, or a combination of these. Currently used chemotherapy (e.g. Methotrexate, Cisplatin and Doxorubicin) is frequently inadequate, with 5
Comparison of chromosomal and array-based comparative genomic hybridization for the detection of genomic imbalances in primary prostate carcinomas
Franclim R Ribeiro, Rui Henrique, Merete Hektoen, Marianne Berg, Carmen Jerónimo, Manuel R Teixeira, Ragnhild A Lothe
Molecular Cancer , 2006, DOI: 10.1186/1476-4598-5-33
Abstract: Our data demonstrate that the reliability of aCGH in the analysis of primary prostate carcinomas depends to some extent on the scoring approach used, with the breakpoint estimation method being the most sensitive and reliable. The pattern of copy number changes detected by aCGH was concordant with that of cCGH, but the higher resolution technique detected 2.7 times more aberrations and 15.2% more carcinomas with genomic imbalances. We additionally show that several aberrations were consistently overlooked using cCGH, such as small deletions at 5q, 6q, 12p, and 17p. The latter were validated by fluorescence in situ hybridization targeting TP53, although only one carcinoma harbored a point mutation in this gene. Strikingly, homozygous deletions at 10q23.31, encompassing the PTEN locus, were seen in 58% of the cases with 10q loss.We conclude that aCGH can significantly improve the detection of genomic aberrations in cancer cells as compared to previously established whole-genome methodologies, although contamination with normal cells may influence the sensitivity and specificity of some scoring approaches. Our work delineated recurrent copy number changes and revealed novel amplified loci and frequent homozygous deletions in primary prostate carcinomas, which may guide future work aimed at identifying the relevant target genes. In particular, biallelic loss seems to be a frequent mechanism of inactivation of the PTEN gene in prostate carcinogenesis.Prostate cancer is a frequent and heterogeneous malignancy with few established prognostic markers. Increased knowledge on the genetic basis of this condition is expected to significantly improve the clinical management of these patients. Most of the genetic data currently available on this malignancy has been obtained using chromosomal comparative genomic hybridization (cCGH), a whole-genome screening methodology well established in the scientific field [1]. We have recently published a statistical dissection of the cCGH da
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.
MGMT promoter methylation in gliomas-assessment by pyrosequencing and quantitative methylation-specific PCR
Annette H?vik, Petter Brandal, Hilde Honne, Hanne-Sofie Dahlback, David Scheie, Merete Hektoen, Torstein Meling, Eirik Helseth, Sverre Heim, Ragnhild A Lothe, Guro Lind
Journal of Translational Medicine , 2012, DOI: 10.1186/1479-5876-10-36
Abstract: We examined 35 low- and 99 high-grade gliomas using quantitative methylation specific PCR (qMSP) and pyrosequencing. Gene expression level of MGMT was analyzed by RT-PCR.When examined by qMSP, 26% of low-grade and 37% of high-grade gliomas were found to be methylated, whereas 97% of low-grade and 55% of high-grade gliomas were found methylated by pyrosequencing. The average MGMT gene expression level was significantly lower in the group of patients with a methylated promoter independent of method used for methylation detection. Primary glioblastoma patients with a methylated MGMT promoter (as evaluated by both methylation detection methods) had approximately 5 months longer median survival compared to patients with an unmethylated promoter (log-rank test; pyrosequencing P = .02, qMSP P = .06). One third of the analyzed samples had conflicting methylation results when comparing the data from the qMSP and pyrosequencing. The overall survival analysis shows that these patients have an intermediate prognosis between the groups with concordant MGMT promoter methylation results when comparing the two methods.In our opinion, MGMT promoter methylation analysis gives sufficient prognostic information to merit its inclusion in the standard management of patients with high-grade gliomas, and in this study pyrosequencing came across as the better analytical method.Gliomas are histologically divided into several subgroups including astrocytomas, oligodendrogliomas, and oligoastrocytomas and are graded from I to IV according to the WHO classification [1]. Prognosis is highly variable depending on histopathology, grade, patient age, and genetic tumor factors such as the presence of a 1p/19q co-deletion, IDH1 and IDH2 mutations, and MGMT promoter methylation [1,2]. The most common glioma subtype in adults is glioblastoma (GBM) with an annual incidence of 3-4/100 000 [1]. This is also the subgroup with the least favorable prognosis. In 2005, Stupp and coworkers reported a 2.5 months
Genomic aberrations in borderline ovarian tumors
Francesca Micci, Lisbeth Haugom, Terje Ahlquist, Hege K Andersen, Vera M Abeler, Ben Davidson, Claes G Trope, Ragnhild A Lothe, Sverre Heim
Journal of Translational Medicine , 2010, DOI: 10.1186/1479-5876-8-21
Abstract: We report a series of borderline ovarian tumors (n = 23) analyzed by G-banding and karyotyping as well as high resolution CGH; in addition, the tumors were analyzed for microsatellite stability status and by FISH for possible 6q deletion.All informative tumors were microsatellite stable and none had a deletion in 6q27. All cases with an abnormal karyotype had simple chromosomal aberrations with +7 and +12 as the most common. In three tumors with single structural rearrangements, a common breakpoint in 3q13 was detected. The major copy number changes detected in the borderline tumors were gains from chromosome arms 2q, 6q, 8q, 9p, and 13q and losses from 1p, 12q, 14q, 15q, 16p, 17p, 17q, 19p, 19q, and 22q. The series included five pairs of bilateral tumors and, in two of these pairs, informative data were obtained as to their clonal relationship. In both pairs, similarities were found between the tumors from the right and left side, strongly indicating that bilaterality had occurred via a metastatic process. The bilateral tumors as a group showed more aberrations than did the unilateral ones, consistent with the view that bilaterality is a sign of more advanced disease.Because some of the imbalances found in borderline ovarian tumors seem to be similar to imbalances already known from the more extensively studied overt ovarian carcinomas, we speculate that the subset of borderline tumors with detectable imbalances or karyotypic aberrations may contain a smaller subset of tumors with a tendency to develop a more malignant phenotype. The group of borderline tumors with no imbalances would, in this line of thinking, have less or no propensity for clonal evolution and development to full-blown carcinomas.Borderline ovarian tumors are of low malignant potential. They exhibit more atypical epithelial proliferation than is seen in adenomas, their benign counterpart, but are without the destructive stromal invasion characteristic of overt adenocarcinomas [1]. Although the cl
DNA methylation profiling of ovarian carcinomas and their in vitro models identifies HOXA9, HOXB5, SCGB3A1, and CRABP1 as novel targets
Qinghua Wu, Ragnhild A Lothe, Terje Ahlquist, Ilvars Silins, Claes G Tropé, Francesca Micci, Jahn M Nesland, Zhenhe Suo, Guro E Lind
Molecular Cancer , 2007, DOI: 10.1186/1476-4598-6-45
Abstract: Eight out of the 13 genes were hypermethylated among the ovarian carcinomas, and altogether 40 of 52 tumours were methylated in one or more genes. Promoter hypermethylation of HOXA9, RASSF1A, APC, CDH13, HOXB5, SCGB3A1 (HIN-1), CRABP1, and MLH1 was found in 51% (26/51), 49% (23/47), 24% (12/51), 20% (10/51), 12% (6/52), 10% (5/52), 4% (2/48), and 2% (1/51) of the carcinomas, respectively, whereas ADAMTS1, MGMT, NR3C1, p14ARF, and p16INK4a were unmethylated in all samples. The methylation frequencies of HOXA9 and SCGB3A1 were higher among relatively early-stage carcinomas (FIGO I-II) than among carcinomas of later stages (FIGO III-IV; P = 0.002, P = 0.020, respectively). The majority of the early-stage carcinomas were of the endometrioid histotype. Additionally, HOXA9 hypermethylation was more common in tumours from patients older than 60 years of age (15/21) than among those of younger age (11/30; P = 0.023). Finally, there was a significant difference in HOXA9 methylation frequency among the histological types (P = 0.007).DNA hypermethylation of tumour suppressor genes seems to play an important role in ovarian carcinogenesis and HOXA9, HOXB5, SCGB3A1, and CRABP1 are identified as novel hypermethylated target genes in this tumour type.Ovarian cancer is often not detected until it has reached an advanced stage and is therefore among the most lethal gynaecological cancer diseases. Tumour stage at diagnosis, residual disease following cytoreductive surgery, and performance status which is evaluated by Karnofsky Index [1] are the three major prognostic factors [2]. Epithelial ovarian carcinoma accounts for over 90% of all cases and includes the following major histological subtypes: serous-, mucinous-, endometrioid-, and clear cell- carcinomas. In Norway, more than 90% of patients with ovarian carcinoma are older than 40 years, with a peak incidence at the age of 75–79 [3].A number of genetic changes have been shown to accumulate during carcinogenesis, including DNA co
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