| 1. |
- Autio, Reija, et al.
(författare)
-
A method for finding putative causes of gene expression variation
- 2004
-
Ingår i: 2nd TICSP Workshop on Computational Systems Biology, WCSB 2004 : Silja Opera, Helsinki-St. Petersburg, June 14 - 16, 2004 - Silja Opera, Helsinki-St. Petersburg, June 14 - 16, 2004. - 1456-2774. - 9521512040 ; 24, s. 29-30
-
Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- The majority of microarray studies evaluate gene ex- pression differences between various specimens or con- ditions. However, the causes of this variability often re- main unknown. Our aim is to identify underlying causes of these patterns, a process that would eventually enable a mechanistic understanding of the deregulation of gene expression in cancer. The procedure consists of three phases: pre-processing, data integration and statistical analysis. We have applied the strategy to identify genes that are overexpressed due to amplification in breast cancer. The data were obtained from 14 breast cancer cell lines, which were subjected to cDNA microarray based copy number and expression experiments. The re- sult of the analysis was a list that consisted of 92 genes. This set includes several genes that are known to be both overexpressed and amplified in breast cancer. The com- plete study was published in Journal of the Franklin In- stitute 2004, and in this paper we focus on the main issues of the study.
|
|
| 2. |
- Hautaniemi, Sampsa, et al.
(författare)
-
A Strategy for Identifying Putative Causes of Gene Expression Variation in Human Cancer
- 2002
-
Ingår i: Workshop on Genomic Signal Processing and Statistics (GENSIPS).
-
Konferensbidrag (refereegranskat)abstract
- There is often a need to predict the impact of alterations in one variable on another variable. This is especially the case in cancer research, where much effort has been made to carry out large-scale gene expression screening by microarray techniques. However, the causes of this variability from one cancer to another and from one gene to another often remain unknown. In this study we present a systematic procedure for finding genes whose expression is altered by an intrinsic or extrinsic explanatory phenomenon. The procedure has three stages: preprocessing, data integration and statistical analysis. We tested and verified the utility of this approach in a study, where expression and copy number of 13,824 genes were determined in 14 breast cancer samples. The expression of 270 genes could be explained by the variability of gene copy number. These genes may represent an important set of primary, genetically “damaged” genes that drive cancer progression.
|
|
| 3. |
- Surakka, Ida, et al.
(författare)
-
The impact of low-frequency and rare variants on lipid levels.
- 2015
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 47:6, s. 589-597
-
Tidskriftsartikel (refereegranskat)abstract
- Using a genome-wide screen of 9.6 million genetic variants achieved through 1000 Genomes Project imputation in 62,166 samples, we identify association to lipid traits in 93 loci, including 79 previously identified loci with new lead SNPs and 10 new loci, 15 loci with a low-frequency lead SNP and 10 loci with a missense lead SNP, and 2 loci with an accumulation of rare variants. In six loci, SNPs with established function in lipid genetics (CELSR2, GCKR, LIPC and APOE) or candidate missense mutations with predicted damaging function (CD300LG and TM6SF2) explained the locus associations. The low-frequency variants increased the proportion of variance explained, particularly for low-density lipoprotein cholesterol and total cholesterol. Altogether, our results highlight the impact of low-frequency variants in complex traits and show that imputation offers a cost-effective alternative to resequencing.
|
|
| 4. |
- Aakula, Anna, et al.
(författare)
-
MicroRNA-135b regulates ERα, AR and HIF1AN and affects breast and prostate cancer cell growth.
- 2015
-
Ingår i: Molecular Oncology. - : Wiley. - 1574-7891. ; 9:7, s. 1287-1300
-
Tidskriftsartikel (refereegranskat)abstract
- MicroRNAs (miRNAs) regulate a wide range of cellular signaling pathways and biological processes in both physiological and pathological states such as cancer. We have previously identified miR-135b as a direct regulator of androgen receptor (AR) protein level in prostate cancer (PCa). We wanted to further explore the relationship of miR-135b to hormonal receptors, particularly estrogen receptor α (ERα). Here we show that miR-135b expression is lower in ERα-positive breast tumors as compared to ERα-negative samples in two independent breast cancer (BCa) patient cohorts (101 and 1302 samples). Additionally, the miR-135b expression is higher in AR-low PCa patient samples (47 samples). We identify ERα as a novel miR-135b target by demonstrating miR-135b binding to the 3'UTR of the ERα and decreased ERα protein and mRNA level upon miR-135b overexpression in BCa cells. MiR-135b reduces proliferation of ERα-positive BCa cells MCF-7 and BT-474 as well as AR-positive PCa cells LNCaP and 22Rv1 when grown in 2D. To identify other genes regulated by miR-135b we performed gene expression studies and found a link to the hypoxia inducible factor 1α (HIF1α) pathway. We show that miR-135b influences the protein level of the inhibitor for hypoxia inducible factor 1α (HIF1AN) and is able to bind to HIF1AN 3'UTR. Our study demonstrates that miR-135b regulates ERα, AR and HIF1AN protein levels through interaction with their 3'UTR regions, and proliferation in ERα-positive BCa and AR-positive PCa cells.
|
|
| 5. |
- Barkardottir, Rosa B, et al.
(författare)
-
Haplotype analysis in Icelandic and Finnish BRCA2 999del5 breast cancer families
- 2001
-
Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1476-5438 .- 1018-4813. ; 9:10, s. 773-779
-
Tidskriftsartikel (refereegranskat)abstract
- The 999del5 mutation is the single, strong BRCA2 founder mutation in Iceland and the most common BRCA1/2 founder mutation in Finland. To evaluate the origin and time since spreading of the 999del5 mutation in Iceland and in Finland, we constructed haplotypes with polymorphic markers within and flanking the BRCA2 gene in a set of 18 Icelandic and 10 Finnish 999del5 breast cancer families. All Icelandic families analysed shared a common core haplotype of about 1.7 cM. The common ancestors for the Icelandic families studied were estimated to trace back to 340-1000 years, not excluding the possibility that the mutation was brought to Iceland during the settlement of the country. Analysis of the Finnish families revealed two distinct haplotypes. A rare one, found in three families in the old settlement region in southwestern Finland, shared a four-marker (0.5 cM) core haplotype with the Icelandic 999del5 haplotype. A distinct approximately 6 cM haplotype was shared by seven 999del5 Finnish families estimated to have a common ancestry 140-300 years ago. These families cluster in two geographical regions in Finland, in the very same area as those with the rare haplotype and also in the most eastern, late settlement region of Finland. The results may indicate a common ancient origin for the 999del5 mutation in Iceland and in Finland, but distinct mutational events cannot be ruled out. The surprising finding of the same mutation in two completely different haplotypes in a sparsely populated area in Finland may suggest gene conversion.
|
|
| 6. |
- Bjorkblom, Benny, et al.
(författare)
-
c-Jun N-Terminal Kinase Phosphorylation of MARCKSL1 Determines Actin Stability and Migration in Neurons and in Cancer Cells
- 2012
-
Ingår i: Molecular and Cellular Biology. - 0270-7306. ; 32:17, s. 3513-3526
-
Tidskriftsartikel (refereegranskat)abstract
- Cell migration is a fundamental biological function, critical during development and regeneration, whereas deregulated migration underlies neurological birth defects and cancer metastasis. MARCKS-like protein 1 (MARCKSL1) is widely expressed in nervous tissue, where, like Jun N-terminal protein kinase (JNK), it is required for neural tube formation, though the mechanism is unknown. Here we show that MARCKSL1 is directly phosphorylated by JNK on C-terminal residues (S120, T148, and T183). This phosphorylation enables MARCKSL1 to bundle and stabilize F-actin, increase filopodium numbers and dynamics, and retard migration in neurons. Conversely, when MARCKSL1 phosphorylation is inhibited, actin mobility increases and filopodium formation is compromised whereas lamellipodium formation is enhanced, as is cell migration. We find that MARCKSL1 mRNA is upregulated in a broad range of cancer types and that MARCKSL1 protein is strongly induced in primary prostate carcinomas. Gene knockdown in prostate cancer cells or in neurons reveals a critical role for MARCKSL1 in migration that is dependent on the phosphorylation state; phosphomimetic MARCKSL1 (MARCKSL1(S120D,T148D,T183D)) inhibits whereas dephospho-MARCKSL(1S120A,T148A,T183A) induces migration. In summary, these data show that JNK phosphorylation of MARCKSL1 regulates actin homeostasis, filopodium and lamellipodium formation, and neuronal migration under physiological conditions and that, when ectopically expressed in prostate cancer cells, MARCKSL1 again determines cell movement.
|
|
| 7. |
- Brennan, Donal, et al.
(författare)
-
The transcription factor Sox11 is a prognostic factor for improved recurrence-free survival in epithelial ovarian cancer
- 2009
-
Ingår i: European Journal of Cancer. - : Elsevier BV. - 1879-0852 .- 0959-8049. ; 45:8, s. 1510-1517
-
Tidskriftsartikel (refereegranskat)abstract
- Abstract Background: Current prognostic molecular markers for epithelial ovarian cancer (EOC) are insufficient. The aim of the current study was to investigate the role of Sox11 in EOC Methods: Using an in silico transcriptomic screen Sox11 was identified as a potential EOC biomarker. Sox11 protein expression was evaluated using immunohistochemistry (IHC) in 76 EOC cases, which were analyzed using automated algorithms to develop a quantitative scoring model. Results: Sox11 mRNA expression was up-regulated in EOC compared to normal tissues. Automated analysis of Sox11 in the EOC cohort revealed high expression of Sox11, in 40% of tumours, who had an improved recurrence free survival (RFS) (p= 0.002). Multivariate analysis confirmed Sox11 was an independent predictor of improved RFS after controlling for stage and grade. Conclusions: These data suggest that Sox11 is a new prognostic marker in EOC. Loss of SOX 11 is associated with a decreased RFS and a more aggressive phenotype.
|
|
| 8. |
- Brockmöller, Scarlet F., et al.
(författare)
-
Integration of metabolomics and expression of glycerol-3-phosphate acyltransferase (GPAM) in breast cancer-link to patient survival, hormone receptor status, and metabolic profiling
- 2012
-
Ingår i: Journal of Proteome Research. - : American Chemical Society (ACS). - 1535-3893 .- 1535-3907. ; 11:2, s. 850-60
-
Tidskriftsartikel (refereegranskat)abstract
- Changes in lipid metabolism are an important but not well-characterized hallmark of cancer. On the basis of our recent findings of lipidomic changes in breast cancer, we investigated glycerol-3-phosphate acyltransferase (GPAM), a key enzyme in the lipid biosynthesis of triacylglycerols and phospholipids. GPAM protein expression was evaluated and linked to metabolomic and lipidomic profiles in a cohort of human breast carcinomas. In addition, GPAM mRNA expression was analyzed using the GeneSapiens in silico transcriptiomics database. High cytoplasmic GPAM expression was associated with hormone receptor negative status (p = 0.013). On the protein (p = 0.048) and mRNA (p = 0.001) levels, increased GPAM expression was associated with a better overall survival. Metabolomic analysis by GC-MS showed that sn-glycerol-3-phosphate, the substrate of GPAM, was elevated in breast cancer compared to normal breast tissue. LC-MS based lipidomic analysis identified significantly higher levels of phospholipids, especially phosphatidylcholines in GPAM protein positive tumors. In conclusion, our results suggest that GPAM is expressed in human breast cancer with associated changes in the cellular metabolism, in particular an increased synthesis of phospholipids, the major structural component of cellular membranes.
|
|
| 9. |
- Brodin, Bertha A., et al.
(författare)
-
Drug sensitivity testing on patient-derived sarcoma cells predicts patient response to treatment and identifies c-Sarc inhibitors as active drugs for translocation sarcomas
- 2019
-
Ingår i: British Journal of Cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 120:4, s. 435-443
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Heterogeneity and low incidence comprise the biggest challenge in sarcoma diagnosis and treatment. Chemotherapy, although efficient for some sarcoma subtypes, generally results in poor clinical responses and is mostly recommended for advanced disease. Specific genomic aberrations have been identified in some sarcoma subtypes but few of them can be targeted with approved drugs. METHODS: We cultured and characterised patient-derived sarcoma cells and evaluated their sensitivity to 525 anti-cancer agents including both approved and non-approved drugs. In total, 14 sarcomas and 5 healthy mesenchymal primary cell cultures were studied. The sarcoma biopsies and derived cells were characterised by gene panel sequencing, cancer driver gene expression and by detecting specific fusion oncoproteins in situ in sarcomas with translocations. RESULTS: Soft tissue sarcoma cultures were established from patient biopsies with a success rate of 58%. The genomic profile and drug sensitivity testing on these samples helped to identify targeted inhibitors active on sarcomas. The cSrc inhibitor Dasatinib was identified as an active drug in sarcomas carrying chromosomal translocations. The drug sensitivity of the patient sarcoma cells ex vivo correlated with the response to the former treatment of the patient. CONCLUSIONS: Our results show that patient-derived sarcoma cells cultured in vitro are relevant and practical models for genotypic and phenotypic screens aiming to identify efficient drugs to treat sarcoma patients with poor treatment options.
|
|
| 10. |
- Catto, James W. F., et al.
(författare)
-
MicroRNA in Prostate, Bladder, and Kidney Cancer: A Systematic Review
- 2011
-
Ingår i: European Urology. - : Elsevier BV. - 1873-7560 .- 0302-2838. ; 59:5, s. 671-681
-
Forskningsöversikt (refereegranskat)abstract
- Context: MicroRNAs (miRNA) are noncoding RNAs that post- transcriptionally regulate gene expression. Their altered expression and function have been observed in most urologic cancers. MiRNAs represent potential disease biomarkers and novel therapeutic targets. Objective: To review and evaluate the evidence implicating miRNAs in the pathogenesis of prostate cancer (PCa), bladder cancer (BCa), and renal cancer. Evidence acquisition: A systematic review was performed using PubMed and Embase to search for reports using strings for microRNA, non- coding RNA, cancer, prostate, bladder, and renal cancer. Identified manuscripts were retrieved and references searched. Selected studies were required to concentrate on the role of miRNA in these urologic cancers. Evidence synthesis: We reviewed articles that focus on this topic. More than 40 miRNAs have been implicated in urologic cancer and many target common carcinogenic pathways. In particular, apoptosis avoidance, cell proliferation, epithelial- to- mesenchymal transition, angiogenic signalling, and the generation of androgen independence are targeted or facilitated by more than one miRNA. Little work has been done to evaluate the translational applications for this knowledge to date. Novel therapeutic strategies have been developed and are under investigation to selectively modulate miRNAs; such work would potentially enable personalised tumour therapy. Conclusions: MiRNAs appear to be important modulators of urologic cancer. Their expression is frequently altered in these tumours, and many are functionally implicated in their pathogenesis. They require evaluation to determine the translational role and therapeutic potential for this knowledge. Crown Copyright (C) 2011 Published by Elsevier B. V. on behalf of European Association of Urology. All rights reserved.
|
|
