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Search Results: 1 - 10 of 9005 matches for " Anne Kallioniemi "
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Rare Copy Number Variants Observed in Hereditary Breast Cancer Cases Disrupt Genes in Estrogen Signaling and TP53 Tumor Suppression Network
Katri Pylk?s,Mikko Vuorela,Meeri Otsukka,Anne Kallioniemi,Arja Jukkola-Vuorinen,Robert Winqvist
PLOS Genetics , 2012, DOI: 10.1371/journal.pgen.1002734
Abstract: Breast cancer is the most common cancer in women in developed countries, and the contribution of genetic susceptibility to breast cancer development has been well-recognized. However, a great proportion of these hereditary predisposing factors still remain unidentified. To examine the contribution of rare copy number variants (CNVs) in breast cancer predisposition, high-resolution genome-wide scans were performed on genomic DNA of 103 BRCA1, BRCA2, and PALB2 mutation negative familial breast cancer cases and 128 geographically matched healthy female controls; for replication an independent cohort of 75 similarly mutation negative young breast cancer patients was used. All observed rare variants were confirmed by independent methods. The studied breast cancer cases showed a consistent increase in the frequency of rare CNVs when compared to controls. Furthermore, the biological networks of the disrupted genes differed between the two groups. In familial cases the observed mutations disrupted genes, which were significantly overrepresented in cellular functions related to maintenance of genomic integrity, including DNA double-strand break repair (P = 0.0211). Biological network analysis in the two independent breast cancer cohorts showed that the disrupted genes were closely related to estrogen signaling and TP53 centered tumor suppressor network. These results suggest that rare CNVs represent an alternative source of genetic variation influencing hereditary risk for breast cancer.
Deciphering downstream gene targets of PI3K/mTOR/p70S6K pathway in breast cancer
Henna Heinonen, Anni Nieminen, Matti Saarela, Anne Kallioniemi, Juha Klefstr?m, Sampsa Hautaniemi, Outi Monni
BMC Genomics , 2008, DOI: 10.1186/1471-2164-9-348
Abstract: Altogether, the silencing of p70S6K altered the expression of 109 and 173 genes in two breast cancer cell lines and 67 genes were altered in both cell lines in addition to RPS6KB1. Furthermore, 17 genes including VTCN1 and CDKN2B showed overlap with genes differentially expressed after PI3K or mTOR inhibition. The gene expression signatures responsive to both PI3K/mTOR pathway and p70S6K inhibitions revealed previously unidentified genes suggesting novel downstream targets for PI3K/mTOR/p70S6K pathway.Since p70S6K overexpression is associated with aggressive disease and poor prognosis of breast cancer patients, the potential downstream targets of p70S6K and the whole PI3K/mTOR/p70S6K pathway identified in our study may have diagnostic value.The 70 kDa ribosomal protein S6 kinase (p70S6K) is a mitogen-activated serine/threonine kinase that has a critical role in control of cell cycle, growth and survival. p70S6K is encoded by RPS6KB1, which is located at 17q23 and is amplified and overexpressed in 10–30% of breast cancer cell lines and primary breast cancers [1-4]. The overexpression of p70S6K is associated with aggressive disease and poor prognosis of breast cancer patients [2]. p70S6 kinase is located downstream of PI3K/AKT/mTOR pathway, which is activated by HER2 receptors, insulin-like growth factor receptor and estrogen receptor in breast cancer [5]. p70S6K itself is activated by 3-phosphoinositide-dependent protein kinase 1 (PDK-1) and mammalian target of rapamycin (mTOR) kinase. p70S6 kinase regulates protein synthesis by activating 40S ribosomal protein S6, leading to an increased rate of translation of the class of 5'TOP (5' terminal oligopyrimide) mRNA transcripts. These transcripts encode critical components of the cellular translational machinery, thus promoting protein synthesis [6,7]. Additionally, p70S6K has a crucial role in cell growth by regulating cell size and progression of cell cycle [8-10]. Recently, p70S6K has been reported to inactivate the p
Array-based gene expression, CGH and tissue data defines a 12q24 gain in neuroblastic tumors with prognostic implication
Maija Wolf, Miikka Korja, Ritva Karhu, Henrik Edgren, Sami Kilpinen, Kalle Ojala, Spyro Mousses, Anne Kallioniemi, Hannu Haapasalo
BMC Cancer , 2010, DOI: 10.1186/1471-2407-10-181
Abstract: A single-gene resolution aCGH profiling was integrated with microarray-based gene expression profiling data to distinguish genetic copy number alterations that were strongly associated with transcriptional changes in two neuroblastoma cell lines. FISH analysis using a hotspot tumor tissue microarray of 37 paraffin-embedded neuroblastoma samples and in silico data mining for gene expression information obtained from previously published studies including up to 445 healthy nervous system samples and 123 neuroblastoma samples were used to evaluate the clinical significance and transcriptional consequences of the detected alterations and to identify subsequently activated gene(s).In addition to the anticipated high-level amplification and subsequent overexpression of MYCN, MEIS1, CDK4 and MDM2 oncogenes, the aCGH analysis revealed numerous other genetic alterations, including microamplifications at 2p and 12q24.11. Most interestingly, we identified and investigated the clinical relevance of a previously poorly characterized amplicon at 12q24.31. FISH analysis showed low-level gain of 12q24.31 in 14 of 33 (42%) neuroblastomas. Patients with the low-level gain had an intermediate prognosis in comparison to patients with MYCN amplification (poor prognosis) and to those with no MYCN amplification or 12q24.31 gain (good prognosis) (P = 0.001). Using the in silico data mining approach, we identified elevated expression of five genes located at the 12q24.31 amplicon in neuroblastoma (DIABLO, ZCCHC8, RSRC2, KNTC1 and MPHOSPH9). Among these, DIABLO showed the strongest activation suggesting a putative role in neuroblastoma progression.The presented systematic and rapid framework, which integrates aCGH, gene expression and tissue data to obtain novel targets and biomarkers for cancer, identified a low-level gain of the 12q24.31 as a potential new biomarker for neuroblastoma progression. Furthermore, results of in silico data mining suggest a new neuroblastoma target gene, DIABLO,
Analysis of BMP4 and BMP7 signaling in breast cancer cells unveils time-dependent transcription patterns and highlights a common synexpression group of genes
Alejandra Rodriguez-Martinez, Emma-Leena Alarmo, Lilli Saarinen, Johanna Ketolainen, Kari Nousiainen, Sampsa Hautaniemi, Anne Kallioniemi
BMC Medical Genomics , 2011, DOI: 10.1186/1755-8794-4-80
Abstract: Both ligands had a strong effect on gene expression, although the response to BMP4 treatment was more pronounced. The cellular functions most strongly affected by BMP signaling were regulation of transcription and development. The observed transcriptional response, as well as its functional outcome, followed a temporal sequence, with regulation of gene expression and signal transduction leading to changes in metabolism and cell proliferation. Hierarchical clustering revealed distinct differences in the response of individual cell lines to BMPs, but also highlighted a synexpression group of genes for both ligands. Interestingly, the majority of the genes within these synexpression groups were shared by the two ligands, probably representing the core molecular responses common to BMP4 and BMP7 signaling pathways.All in all, we show that BMP signaling has a remarkable effect on gene transcription in breast cancer cells and that the functions affected follow a logical temporal pattern. Our results also uncover components of the common cellular transcriptional response to BMP4 and BMP7. Most importantly, this study provides a list of potential novel BMP target genes relevant in breast cancer.Bone morphogenetic proteins (BMPs) are extracellular ligand molecules that belong to the transforming growth factor β (TGF-β) superfamily. To date, 21 members of the human BMP family have been identified [1]. BMPs regulate transcription of target genes by signaling through type I and II transmembrane serine-threonine receptors. Binding of the ligand to the type II receptor elicits phosphorylation of the type I receptor, which, as a result, is able to phosphorylate other molecules and transmit the signal. In the canonical BMP pathway, the type I receptor phosphorylates receptor-regulated SMAD (homologue of Drosophila Mothers Against Decapentaplegic) proteins (R-SMADs, SMAD-1/5/8), which then bind to the common mediator SMAD4; the resulting SMAD complex translocates to the nucleus to r
Headmaster′s Conceptions of the Finnish Religious Education - Solution from the Perspective of Human Rights
Arto Kallioniemi,Mia Matilainen
Nordidactica : Journal of Humanities and Social Science Education , 2011,
Abstract: There has been much discussion about the most suitable model of religious education (RE hereafter) in public schools all around Europe. The Finnish model of RE has attracted great interest, because in Finland RE is given according to one’s own religion. The Finnish model of RE is very unique and it emphasises the right of religious minorities to participate in RE according to their own religion in state-owned schools. In this article we examine headmasters’ conceptions of the current Finnish RE solution from the perspective of human rights. The study is based on qualitative interviews.Headmasters presented both advantages and disadvantages of the current RE solution. These advantages are briefly: freedom of religion, an opportunity to get RE according to one′s own religion, knowing one′s own roots, an opportunity to understand people from different religious backgrounds and an opportunity to study other religions for those students who are not members of religious communities. The limits of the solution are that it puts students into their own religious groups and this limits possibilities for religious dialogue, which should be one of the key elements of modern RE. RE has a strong potential to promote human rights. It is important to discuss different models of arranging education from the viewpoint of human rights. The human rights viewpoint should be central when dealing with the aims, contents and organization structure of RE. Different interpretations of religious freedom and the right to religious education are important considerations especially for RE.
Identification of fusion genes in breast cancer by paired-end RNA-sequencing
Henrik Edgren, Astrid Murumagi, Sara Kangaspeska, Daniel Nicorici, Vesa Hongisto, Kristine Kleivi, Inga H Rye, Sandra Nyberg, Maija Wolf, Anne-Lise Borresen-Dale, Olli Kallioniemi
Genome Biology , 2011, DOI: 10.1186/gb-2011-12-1-r6
Abstract: We applied paired-end RNA-seq to identify 24 novel and 3 previously known fusion genes in breast cancer cells. Supported by an improved bioinformatic approach, we had a 95% success rate of validating gene fusions initially detected by RNA-seq. Fusion partner genes were found to contribute promoters (5' UTR), coding sequences and 3' UTRs. Most fusion genes were associated with copy number transitions and were particularly common in high-level DNA amplifications. This suggests that fusion events may contribute to the selective advantage provided by DNA amplifications and deletions. Some of the fusion partner genes, such as GSDMB in the TATDN1-GSDMB fusion and IKZF3 in the VAPB-IKZF3 fusion, were only detected as a fusion transcript, indicating activation of a dormant gene by the fusion event. A number of fusion gene partners have either been previously observed in oncogenic gene fusions, mostly in leukemias, or otherwise reported to be oncogenic. RNA interference-mediated knock-down of the VAPB-IKZF3 fusion gene indicated that it may be necessary for cancer cell growth and survival.In summary, using RNA-sequencing and improved bioinformatic stratification, we have discovered a number of novel fusion genes in breast cancer, and identified VAPB-IKZF3 as a potential fusion gene with importance for the growth and survival of breast cancer cells.Gene fusions are a well-known mechanism for oncogene activation in leukemias, lymphomas and sarcomas, with the BCR-ABL fusion gene in chronic myeloid leukemia as the prototype example [1,2]. The recent identification of recurrent ETS-family translocations in prostate cancer [3] and EML4-ALK in lung cancer [4] now suggests that fusion genes may play an important role also in the development of epithelial cancers. The reason why they were not previously detected was the lack of suitable techniques to identify balanced recurrent chromosomal aberrations in the often chaotic karyotypic profiles of solid tumors.Massively parallel RNA-seq
Characterization of Non-Specific Cytotoxic Cell Receptor Protein 1: A New Member of the Lectin-Type Subfamily of F-Box Proteins
Heini Kallio, Martti Tolvanen, Janne J?nis, Pei-wen Pan, Eeva Laurila, Anne Kallioniemi, Sami Kilpinen, Vilppu J. Tuominen, Jorma Isola, Jarkko Valjakka, Silvia Pastorekova, Jaromir Pastorek, Seppo Parkkila
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0027152
Abstract: Our previous microarray study showed that the non-specific cytotoxic cell receptor protein 1 (Nccrp1) transcript is significantly upregulated in the gastric mucosa of carbonic anhydrase IX (CA IX)-deficient (Car9?/?) mice. In this paper, we aimed to characterize human NCCRP1 and to elucidate its relationship to CA IX. Recombinant NCCRP1 protein was expressed in Escherichia coli, and a novel polyclonal antiserum was raised against the purified full-length protein. Immunocytochemistry showed that NCCRP1 is expressed intracellularly, even though it has previously been described as a transmembrane protein. Using bioinformatic analyses, we identified orthologs of NCCRP1 in 35 vertebrate genomes, and up to five paralogs per genome. These paralogs are FBXO genes whose protein products are components of the E3 ubiquitin ligase complexes. NCCRP1 proteins have no signal peptides or transmembrane domains. NCCRP1 has mainly been studied in fish and was thought to be responsible for the cytolytic function of nonspecific cytotoxic cells (NCCs). Our analyses showed that in humans, NCCRP1 mRNA is expressed in tissues containing squamous epithelium, whereas it shows a more ubiquitous tissue expression pattern in mice. Neither human nor mouse NCCRP1 expression is specific to immune tissues. Silencing CA9 using siRNAs did not affect NCCRP1 levels, indicating that its expression is not directly regulated by CA9. Interestingly, silencing NCCRP1 caused a statistically significant decrease in the growth of HeLa cells. These studies provide ample evidence that the current name, “non-specific cytotoxic cell receptor protein 1,” is not appropriate. We therefore propose that the gene name be changed to FBXO50.
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
Analysis of Kinase Gene Expression Patterns across 5681 Human Tissue Samples Reveals Functional Genomic Taxonomy of the Kinome
Sami Kilpinen,Kalle Ojala,Olli Kallioniemi
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0015068
Abstract: Kinases play key roles in cell signaling and represent major targets for drug development, but the regulation of their activation and their associations with health and disease have not been systematically analyzed. Here, we carried out a bioinformatic analysis of the expression levels of 459 human kinase genes in 5681 samples consisting of 44 healthy and 55 malignant human tissues. Defining the tissues where the kinase genes were transcriptionally active led to a functional genomic taxonomy of the kinome and a classification of human tissues and disease types based on the similarity of their kinome gene expression. The co-expression network around each of the kinase genes was defined in order to determine the functional context, i.e. the biological processes that were active in the cells and tissues where the kinase gene was expressed. Strong associations for individual kinases were found for mitosis (69 genes, including AURKA and BUB1), cell cycle control (73 genes, including PLK1 and AURKB), DNA repair (49 genes, including CHEK1 and ATR), immune response (72 genes, including MATK), neuronal (131 genes, including PRKCE) and muscular (72 genes, including MYLK2) functions. We then analyzed which kinase genes gain or lose transcriptional activity in the development of prostate and lung cancers and elucidated the functional associations of individual cancer associated kinase genes. In summary, we report here a systematic classification of kinases based on the bioinformatic analysis of their expression in human tissues and diseases, as well as grouping of tissues and tumor types according to the similarity of their kinome transcription.
Chemical Biology Drug Sensitivity Screen Identifies Sunitinib as Synergistic Agent with Disulfiram in Prostate Cancer Cells
Kirsi Ketola, Olli Kallioniemi, Kristiina Iljin
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0051470
Abstract: Background Current treatment options for castration- and treatment-resistant prostate cancer are limited and novel approaches are desperately needed. Our recent results from a systematic chemical biology sensitivity screen covering most known drugs and drug-like molecules indicated that aldehyde dehydrogenase inhibitor disulfiram is one of the most potent cancer-specific inhibitors of prostate cancer cell growth, including TMPRSS2-ERG fusion positive cancers. However, the results revealed that disulfiram alone does not block tumor growth in vivo nor induce apoptosis in vitro, indicating that combinatorial approaches may be required to enhance the anti-neoplastic effects. Methods and Findings In this study, we utilized a chemical biology drug sensitivity screen to explore disulfiram mechanistic details and to identify compounds potentiating the effect of disulfiram in TMPRSS2-ERG fusion positive prostate cancer cells. In total, 3357 compounds including current chemotherapeutic agents as well as drug-like small molecular compounds were screened alone and in combination with disulfiram. Interestingly, the results indicated that androgenic and antioxidative compounds antagonized disulfiram effect whereas inhibitors of receptor tyrosine kinase, proteasome, topoisomerase II, glucosylceramide synthase or cell cycle were among compounds sensitizing prostate cancer cells to disulfiram. The combination of disulfiram and an antiangiogenic agent sunitinib was studied in more detail, since both are already in clinical use in humans. Disulfiram-sunitinib combination induced apoptosis and reduced androgen receptor protein expression more than either of the compounds alone. Moreover, combinatorial exposure reduced metastatic characteristics such as cell migration and 3D cell invasion as well as induced epithelial differentiation shown as elevated E-cadherin expression. Conclusions Taken together, our results propose novel combinatorial approaches to inhibit prostate cancer cell growth. Disulfiram-sunitinib combination was identified as one of the potent synergistic approaches. Since sunitinib alone has been reported to lack efficacy in prostate cancer clinical trials, our results provide a rationale for novel combinatorial approach to target prostate cancer more efficiently.
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