| 1. |
- Davidsson, Josef, et al.
(author)
-
Constitutional trisomy 8 mosaicism as a model for epigenetic studies of aneuploidy.
- 2013
-
In: Epigenetics & Chromatin. - : Springer Science and Business Media LLC. - 1756-8935. ; 6:1
-
Journal article (peer-reviewed)abstract
- To investigate epigenetic patterns associated with aneuploidy we used constitutional trisomy 8 mosaicism (CT8M) as a model, enabling analyses of single cell clones, harboring either trisomy or disomy 8, from the same patient; this circumvents any bias introduced by using cells from unrelated, healthy individuals as controls. We profiled gene and miRNA expression as well as genome-wide and promoter specific DNA methylation and hydroxymethylation patterns in trisomic and disomic fibroblasts, using microarrays and methylated DNA immunoprecipitation.
|
|
| 2. |
|
|
| 3. |
- Frings, Oliver, et al.
(author)
-
Prognostic Significance in Breast Cancer of a Gene Signature Capturing Stromal PDGF Signaling
- 2013
-
In: American Journal of Pathology. - : Elsevier BV. - 0002-9440 .- 1525-2191. ; 182:6, s. 2037-2047
-
Journal article (peer-reviewed)abstract
- In this study, we describe a novel gene expression signature of platelet-derived growth factor (PDGF) activated fibroblasts, which is able to identify breast cancers with a PDGF-stimulated fibroblast stroma and displays an independent and strong prognostic significance. Global gene expression was compared between PDGF-stimulated human fibroblasts and cultured resting fibroblasts. The most differentially expressed genes were reduced to a gene expression signature of 113 genes. The biological significance and prognostic capacity of this signature were investigated using four independent clinical breast cancer data sets. Concomitant high expression of PDGF beta receptor and its cognate Ligands is associated with a high PDGF signature score. This supports the notion that the signature detects tumors with PDGF-activated stroma. Subsequent analyses indicated significant associations between high PDGF signature score and clinical characteristics, including human epidermal growth factor receptor 2 positivity, estrogen receptor negativity, high tumor grade, and large tumor size. A high PDGF signature score is associated with shorter survival in univariate analysis. Furthermore, the high PDGF signature score acts as a significant marker of poor prognosis in multivariate survival analyses, including classic prognostic markers, Ki-67 status, a proliferation gene signature, or other recently described stroma-derived gene expression signatures.
|
|
| 4. |
- Hansén Nord, Karolin, et al.
(author)
-
Retained heterodisomy is associated with high gene expression in hyperhaploid inflammatory leiomyosarcoma.
- 2012
-
In: Neoplasia. - : Elsevier BV. - 1522-8002. ; 14:9, s. 807-U156
-
Journal article (peer-reviewed)abstract
- Inflammatory leiomyosarcoma (ILMS) is a soft tissue tumor that morphologically resembles conventional leiomyosarcoma (LMS) admixed with a prominent inflammatory infiltrate. Genetic data on ILMS are still limited but have suggested that this entity is characterized by hyperhaploidy (24-34 chromosomes). This low chromosome number is otherwise uncommon in neoplasia and has been found only in 0.2% to 0.3% of cytogenetically investigated tumors. Here, three ILMS were investigated using cytogenetic, single-nucleotide polymorphism (SNP) array, and global gene expression analyses. All cases displayed a hyperhaploid origin. Combined with previously reported cases, hyperhaploidy has been found in six of seven cytogenetically investigated ILMS. The copy number distribution of individual chromosomes is clearly nonrandom; the hyperhaploid clones of all six cases displayed disomy for chromosomes 5 and 20, and two copies of chromosomes 18, 21, and 22 were also common. All chromosomes identified as disomic showed a biparental origin by SNP array analysis; whether this is of pathogenetic importance is not known. Compared with conventional LMS, ILMS had a distinct gene expression signature. Furthermore, the number of chromosome copies correlated well with gene expression levels; disomic chromosomes showed higher gene expression levels than monosomic chromosomes, a finding that has not previously been reported for hyperhaploid tumors. Taken together, our findings suggest that disomy for some chromosomes, notably 5 and 20, as well as distorted gene expression achieved through massive loss of other chromosomes are essential features of ILMS.
|
|
| 5. |
- Lauss, Martin, et al.
(author)
-
DNA methylation analyses of urothelial carcinoma reveal distinct epigenetic subtypes and an association between gene copy number and methylation status.
- 2012
-
In: Epigenetics. - : Informa UK Limited. - 1559-2294 .- 1559-2308. ; 7:8, s. 858-867
-
Journal article (peer-reviewed)abstract
- We assessed DNA methylation and copy number status of 27,000 CpGs in 149 urothelial carcinomas and integrated the findings with gene expression and mutation data. Methylation was associated with gene expression for 1,332 CpGs, of which 26% showed positive correlation with expression, i.e., high methylation and high gene expression levels. These positively correlated CpGs were part of specific transcription factor binding sites, such as sites for MYC and CREBP1, or located in gene bodies. Furthermore, we found genes with copy number gains, low expression and high methylation levels, revealing an association between methylation and copy number levels. This phenomenon was typically observed for developmental genes, such as HOX genes, and tumor suppressor genes. In contrast, we also identified genes with copy number gains, high expression and low methylation levels. This was for instance observed for some keratin genes. Tumor cases could be grouped into four subgroups, termed epitypes, by their DNA methylation profiles. One epitype was influenced by the presence of infiltrating immune cells, two epitypes were mainly composed of non-muscle invasive tumors, and the remaining epitype of muscle invasive tumors. The polycomb complex protein EZH2 that blocks differentiation in embryonic stem cells showed increased expression both at the mRNA and protein levels in the muscle invasive epitype, together with methylation of polycomb target genes and HOX genes. Our data highlights HOX gene silencing and EZH2 expression as mechanisms to promote a more undifferentiated and aggressive state in UC.
|
|
| 6. |
- Lindgren, David, et al.
(author)
-
Combined Gene Expression and Genomic Profiling Define Two Intrinsic Molecular Subtypes of Urothelial Carcinoma and Gene Signatures for Molecular Grading and Outcome
- 2010
-
In: Cancer Research. - 0008-5472 .- 1538-7445. ; 70:9, s. 3463-3472
-
Journal article (peer-reviewed)abstract
- In the present investigation, we sought to refine the classification of urothelial carcinoma by combining information on gene expression, genomic, and gene mutation levels. For these purposes, we performed gene expression analysis of 144 carcinomas, and whole genome array-CGH analysis and mutation analyses of FGFR3, PIK3CA, KRAS, HRAS, NRAS, TP53, CDKN2A, and TSC1 in 103 of these cases. Hierarchical cluster analysis identified two intrinsic molecular subtypes, MS1 and MS2, which were validated and defined by the same set of genes in three independent bladder cancer data sets. The two subtypes differed with respect to gene expression and mutation profiles, as well as with the level of genomic instability. The data show that genomic instability was the most distinguishing genomic feature of MS2 tumors, and that this trait was not dependent on TP53/MDM2 alterations. By combining molecular and pathologic data, it was possible to distinguish two molecular subtypes of T(a) and T(1) tumors, respectively. In addition, we define gene signatures validated in two independent data sets that classify urothelial carcinoma into low-grade (G(1)/G(2)) and high-grade (G(3)) tumors as well as non-muscle and muscle-invasive tumors with high precisions and sensitivities, suggesting molecular grading as a relevant complement to standard pathologic grading. We also present a gene expression signature with independent prognostic effect on metastasis and disease-specific survival. We conclude that the combination of molecular and histopathologic classification systems might provide a strong improvement for bladder cancer classification and produce new insights into the development of this tumor type.
|
|
| 7. |
- Möller, Emely, et al.
(author)
-
FUS-CREB3L2/L1-Positive Sarcomas Show a Specific Gene Expression Profile with Upregulation of CD24 and FOXL1.
- 2011
-
In: Clinical Cancer Research. - 1078-0432. ; 17:9, s. 2646-2656
-
Journal article (peer-reviewed)abstract
- Abstract PURPOSE: Low-grade fibromyxoid sarcoma (LGFMS) is typically characterized by the specific translocation t(7;16)(q33;p11) and the corresponding fusion gene FUS-CREB3L2. The present study aimed to extract LGFMS-specific, and putatively FUS-CREB3L2-dependent, gene expression patterns to learn more about the pathogenesis of this tumor. EXPERIMENTAL DESIGN: We carried out single nucleotide polymorphism (SNP) and global gene expression array analyses, and/or immunohistochemical (IHC) analyses on 24 LGFMS tumor biopsies. Tumor types that are important differential diagnoses to LGFMS were included as comparison in the gene and protein expression analyses. In addition, cells that stably expressed FUS-CREB3L2 were analyzed with gene expression array and the influence of FUS-CREB3L2 on gene expression was investigated in vitro. RESULTS: The SNP array analysis detected recurrent microdeletions in association with the t(7;16) chromosomal breakpoints and gain of 7q in cases with ring chromosomes. Gene expression analysis clearly distinguished LGFMS from morphologically similar tumors and MUC4 was identified as a potential diagnostic marker for LGFMS by gene expression and IHC analysis. FOXL1 was identified as the top upregulated gene in LGFMS and CD24 was upregulated in both LGFMS tumors and FUS-CREB3L2 expressing cells. FUS-CREB3L2 was capable of activating transcription from CD24 regulatory sequences in luciferase assays, suggesting an important role for the upregulation of this gene in LGFMS. CONCLUSIONS: The gene expression profile of LGFMS is distinct from that of soft tissue tumors with similar morphology. The data could be used to identify a potential diagnostic marker for LGFMS and to identify possible FUS-CREB3L2 regulated genes. Clin Cancer Res; 17(9); 2646-56. ©2011 AACR.
|
|
| 8. |
- Pena, Cristina, et al.
(author)
-
STC1 Expression By Cancer-Associated Fibroblasts Drives Metastasis of Colorectal Cancer
- 2013
-
In: Cancer Research. - : American Association for Cancer Research. - 0008-5472 .- 1538-7445. ; 74:4, s. 1287-1297
-
Journal article (peer-reviewed)abstract
- Platelet-derived growth factor (PDGF) receptor signaling is a major functional determinant of cancer-associated fibroblasts (CAF). Elevated expression of PDGF receptors on stromal CAFs is associated with metastasis and poor prognosis, but mechanism(s) that underlie these connections are not understood. Here, we report the identification of the secreted glycoprotein stanniocalcin-1 (STC1) as a mediator of metastasis by PDGF receptor function in the setting of colorectal cancer. PDGF-stimulated fibroblasts increased migration and invasion of cocultured colorectal cancer cells in an STC1-dependent manner. Analyses of human colorectal cancers revealed significant associations between stromal PDGF receptor and STC1 expression. In an orthotopic mouse model of colorectal cancer, tumors formed in the presence of STC1-deficient fibroblasts displayed reduced intravasation of tumor cells along with fewer and smaller distant metastases formed. Our results reveal a mechanistic basis for understanding the contribution of PDGF-activated CAFs to cancer metastasis. Cancer Res; 73(4); 1287-97.
|
|
| 9. |
|
|
| 10. |
- Roupé, Karl Markus, et al.
(author)
-
Transcription Factor Binding Site Analysis Identifies FOXO Transcription Factors as Regulators of the Cutaneous Wound Healing Process.
- 2014
-
In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:2
-
Journal article (peer-reviewed)abstract
- The search for significantly overrepresented and co-occurring transcription factor binding sites in the promoter regions of the most differentially expressed genes in microarray data sets could be a powerful approach for finding key regulators of complex biological processes. To test this concept, two previously published independent data sets on wounded human epidermis were re-analyzed. The presence of co-occurring transcription factor binding sites for FOXO1, FOXO3 and FOXO4 in the majority of the promoter regions of the most significantly differentially expressed genes between non-wounded and wounded epidermis implied an important role for FOXO transcription factors during wound healing. Expression levels of FOXO transcription factors during wound healing in vivo in both human and mouse skin were analyzed and a decrease for all FOXOs in human wounded skin was observed, with FOXO3 having the highest expression level in non wounded skin. Impaired re-epithelialization was found in cultures of primary human keratinocytes expressing a constitutively active variant of FOXO3. Conversely knockdown of FOXO3 in keratinocytes had the opposite effect and in an in vivo mouse model with FOXO3 knockout mice we detected significantly accelerated wound healing. This article illustrates that the proposed approach is a viable method for identifying important regulators of complex biological processes using in vivo samples. FOXO3 has not previously been implicated as an important regulator of wound healing and its exact function in this process calls for further investigation.
|
|
