19 results on '"Jo Anders Rønneberg"'
Search Results
2. miRNA-mRNA integrated analysis reveals roles for miRNAs in primary breast tumors.
- Author
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Espen Enerly, Israel Steinfeld, Kristine Kleivi, Suvi-Katri Leivonen, Miriam R Aure, Hege G Russnes, Jo Anders Rønneberg, Hilde Johnsen, Roy Navon, Einar Rødland, Rami Mäkelä, Bjørn Naume, Merja Perälä, Olli Kallioniemi, Vessela N Kristensen, Zohar Yakhini, and Anne-Lise Børresen-Dale
- Subjects
Medicine ,Science - Abstract
IntroductionFew studies have performed expression profiling of both miRNA and mRNA from the same primary breast carcinomas. In this study we present and analyze data derived from expression profiling of 799 miRNAs in 101 primary human breast tumors, along with genome-wide mRNA profiles and extensive clinical information.MethodsWe investigate the relationship between these molecular components, in terms of their correlation with each other and with clinical characteristics. We use a systems biology approach to examine the correlative relationship between miRNA and mRNAs using statistical enrichment methods.ResultsWe identify statistical significant differential expression of miRNAs between molecular intrinsic subtypes, and between samples with different levels of proliferation. Specifically, we point to miRNAs significantly associated with TP53 and ER status. We also show that several cellular processes, such as proliferation, cell adhesion and immune response, are strongly associated with certain miRNAs. We validate the role of miRNAs in regulating proliferation using high-throughput lysate-microarrays on cell lines and point to potential drivers of this process.ConclusionThis study provides a comprehensive dataset as well as methods and system-level results that jointly form a basis for further work on understanding the role of miRNA in primary breast cancer.
- Published
- 2011
- Full Text
- View/download PDF
3. Supplementary Table 1 from GSTP1 Promoter Haplotypes Affect DNA Methylation Levels and Promoter Activity in Breast Carcinomas
- Author
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Vessela N. Kristensen, Odd S. Gabrielsen, Anne-Lise Børresen-Dale, Per Eystein Lønning, Ivo G. Gut, Zohar Yakhini, Elen M. Brendeford, Fredrik E. Johansen, Grethe I.G. Alnaes, Hiroko K. Solvang, Jörg Tost, and Jo Anders Rønneberg
- Abstract
Supplementary Table 1 from GSTP1 Promoter Haplotypes Affect DNA Methylation Levels and Promoter Activity in Breast Carcinomas
- Published
- 2023
4. Data from GSTP1 Promoter Haplotypes Affect DNA Methylation Levels and Promoter Activity in Breast Carcinomas
- Author
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Vessela N. Kristensen, Odd S. Gabrielsen, Anne-Lise Børresen-Dale, Per Eystein Lønning, Ivo G. Gut, Zohar Yakhini, Elen M. Brendeford, Fredrik E. Johansen, Grethe I.G. Alnaes, Hiroko K. Solvang, Jörg Tost, and Jo Anders Rønneberg
- Abstract
The CpG island spanning the transcription start of the glutathione S-transferase P1 becomes methylated in a variety of human cancers including breast cancer. To study the effect of sequence variation on hypermethylation of the GSTP1 promoter, we analyzed the genetic and epigenetic variability in 90 tumors from patients with locally advanced breast cancer. High-resolution quantitative analysis revealed large variability in the DNA methylation levels. Lack of methylation was more often observed in the basal and normal-like estrogen receptor (ER)-negative tumors, and methylated GSTP1 was associated with better overall survival (P = 0.00063). Studies of the genetic variation identified 14 different haplotypes. The distribution of methylation levels of tumors homozygous for the most frequent haplotype was significantly different from other haplotype combinations (P = 0.011), the difference being more pronounced in ER-positive (P = 0.005) and progesterone receptor–positive (P = 0.008) tumors. Regression modeling identified the ER status and haplotype as the main determinants of DNA methylation variability. We identified a putative c-Myb response element (MRE) that was present in one of two minimal promoter haplotypes. In vitro analysis showed that c-Myb binds to the MRE, but binding was weakened by the two polymorphisms. Transient cotransfections in luminal-type and basal-like breast cancer cell lines confirmed cell-specific differential binding of c-Myb to the polymorphic sites, leading to a change in the expression from the GSTP1 promoter in vivo. GSTP1 expression was moderately but significantly (P = 0.01) reduced after siRNA-mediated knockdown of c-Myb. Our results indicate that haplotype structure of a promoter is important for the extent of DNA methylation. [Cancer Res 2008;68(14):5562–71]
- Published
- 2023
5. Supplementary Table 2 from GSTP1 Promoter Haplotypes Affect DNA Methylation Levels and Promoter Activity in Breast Carcinomas
- Author
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Vessela N. Kristensen, Odd S. Gabrielsen, Anne-Lise Børresen-Dale, Per Eystein Lønning, Ivo G. Gut, Zohar Yakhini, Elen M. Brendeford, Fredrik E. Johansen, Grethe I.G. Alnaes, Hiroko K. Solvang, Jörg Tost, and Jo Anders Rønneberg
- Abstract
Supplementary Table 2 from GSTP1 Promoter Haplotypes Affect DNA Methylation Levels and Promoter Activity in Breast Carcinomas
- Published
- 2023
6. Supplementary Figure 1 from GSTP1 Promoter Haplotypes Affect DNA Methylation Levels and Promoter Activity in Breast Carcinomas
- Author
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Vessela N. Kristensen, Odd S. Gabrielsen, Anne-Lise Børresen-Dale, Per Eystein Lønning, Ivo G. Gut, Zohar Yakhini, Elen M. Brendeford, Fredrik E. Johansen, Grethe I.G. Alnaes, Hiroko K. Solvang, Jörg Tost, and Jo Anders Rønneberg
- Abstract
Supplementary Figure 1 from GSTP1 Promoter Haplotypes Affect DNA Methylation Levels and Promoter Activity in Breast Carcinomas
- Published
- 2023
7. Supplementary Table 4 from GSTP1 Promoter Haplotypes Affect DNA Methylation Levels and Promoter Activity in Breast Carcinomas
- Author
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Vessela N. Kristensen, Odd S. Gabrielsen, Anne-Lise Børresen-Dale, Per Eystein Lønning, Ivo G. Gut, Zohar Yakhini, Elen M. Brendeford, Fredrik E. Johansen, Grethe I.G. Alnaes, Hiroko K. Solvang, Jörg Tost, and Jo Anders Rønneberg
- Abstract
Supplementary Table 4 from GSTP1 Promoter Haplotypes Affect DNA Methylation Levels and Promoter Activity in Breast Carcinomas
- Published
- 2023
8. Supplementary Table 3 from GSTP1 Promoter Haplotypes Affect DNA Methylation Levels and Promoter Activity in Breast Carcinomas
- Author
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Vessela N. Kristensen, Odd S. Gabrielsen, Anne-Lise Børresen-Dale, Per Eystein Lønning, Ivo G. Gut, Zohar Yakhini, Elen M. Brendeford, Fredrik E. Johansen, Grethe I.G. Alnaes, Hiroko K. Solvang, Jörg Tost, and Jo Anders Rønneberg
- Abstract
Supplementary Table 3 from GSTP1 Promoter Haplotypes Affect DNA Methylation Levels and Promoter Activity in Breast Carcinomas
- Published
- 2023
9. Methylation profiling with a panel of cancer related genes: Association with estrogen receptor, TP53 mutation status and expression subtypes in sporadic breast cancer
- Author
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Vessela N. Kristensen, Hiroko K. Solvang, Jo Anders Rønneberg, Silje H. Nordgard, Ida Rashida Khan Bukholm, Bjørn Naume, Jörg Tost, Ivo Gut, Thomas Fleischer, Christian Daviaud, Anne Lise Børresen-Dale, Ivan Potapenko, Daniel Nebdal, and Hege Edvardsen
- Subjects
TBX1 ,Cancer Research ,Estrogen receptor ,Breast Neoplasms ,Biology ,Breast cancer ,Genetics ,medicine ,Humans ,RNA, Messenger ,Epigenetics ,Estrogen Receptor Status ,General Medicine ,Methylation ,DNA Methylation ,medicine.disease ,Receptors, Estrogen ,Oncology ,CpG site ,Mutation ,Papers ,DNA methylation ,Cancer research ,Molecular Medicine ,Female ,Tumor Suppressor Protein p53 - Abstract
Breast cancer is a heterogeneous disease that can be divided in subtypes based on histology, gene expression profiles as well as differences in genomic aberrations. Distinct global DNA methylation profiles have been reported in normal breast epithelial cells as well as in breast tumors. However, the influence of the tumor methylome on the previously described subgroups of breast cancer is not fully understood. Here we report the DNA methylation profiles of 80 breast tumors using a panel of 807 cancer related genes interrogating 1505 CpG sites. We identified three major clusters based on the methylation profiles; one consisting of mainly tumors of myoepithelial origin and two other clusters with tumors of predominantly luminal epithelial origin. The clusters were different with respect to estrogen receptor status, TP53 status, ErbB2 status and grade. The most significantly differentially methylated genes including HDAC1, TFF1, OGG1, BMP3, FZD9 and HOXA11 were confirmed by pyrosequencing. Gene Ontology analysis revealed enrichment for genes involved in developmental processes including homeobox domain genes (HOXA9, HOXA11, PAX6, MYBL2, ISL1 and IPF1) and (ETS1, HDAC1, CREBBP, GAS7, SPI1 and TBX1). Extensive correlation to mRNA expression was observed. Pathway analyses identified a significant association with canonical (curated) pathways such as hepatic fibrosis including genes like EGF, NGFR and TNF, dendritic cell maturation and the NF‐κB signaling pathway. Our results show that breast tumor expression subtypes harbor major epigenetic differences and tumors with similar gene expression profiles might belong to epigenetically different subtypes. Some of the transcription factors identified, with key roles in differentiation and development might play a role in inducing and maintaining the different phenotypes.
- Published
- 2010
10. GSTP1 Promoter Haplotypes Affect DNA Methylation Levels and Promoter Activity in Breast Carcinomas
- Author
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Per Eystein Lønning, Ivo Gut, Grethe I. Grenaker Alnæs, Odd S. Gabrielsen, Fredrik E. Johansen, Jo Anders Rønneberg, Zohar Yakhini, Jörg Tost, Anne Lise Børresen-Dale, Elen M. Brendeford, Vessela N. Kristensen, and Hiroko K. Solvang
- Subjects
Cancer Research ,Response element ,Breast Neoplasms ,Biology ,Response Elements ,Epigenesis, Genetic ,Proto-Oncogene Proteins c-myb ,GSTP1 ,Genetic variation ,Humans ,Epigenetics ,RNA, Small Interfering ,Promoter Regions, Genetic ,Polymorphism, Genetic ,Haplotype ,Methylation ,DNA Methylation ,Glutathione S-Transferase pi ,Haplotypes ,Receptors, Estrogen ,Oncology ,CpG site ,DNA methylation ,Cancer research ,Regression Analysis ,CpG Islands ,Protein Binding - Abstract
The CpG island spanning the transcription start of the glutathione S-transferase P1 becomes methylated in a variety of human cancers including breast cancer. To study the effect of sequence variation on hypermethylation of the GSTP1 promoter, we analyzed the genetic and epigenetic variability in 90 tumors from patients with locally advanced breast cancer. High-resolution quantitative analysis revealed large variability in the DNA methylation levels. Lack of methylation was more often observed in the basal and normal-like estrogen receptor (ER)-negative tumors, and methylated GSTP1 was associated with better overall survival (P = 0.00063). Studies of the genetic variation identified 14 different haplotypes. The distribution of methylation levels of tumors homozygous for the most frequent haplotype was significantly different from other haplotype combinations (P = 0.011), the difference being more pronounced in ER-positive (P = 0.005) and progesterone receptor–positive (P = 0.008) tumors. Regression modeling identified the ER status and haplotype as the main determinants of DNA methylation variability. We identified a putative c-Myb response element (MRE) that was present in one of two minimal promoter haplotypes. In vitro analysis showed that c-Myb binds to the MRE, but binding was weakened by the two polymorphisms. Transient cotransfections in luminal-type and basal-like breast cancer cell lines confirmed cell-specific differential binding of c-Myb to the polymorphic sites, leading to a change in the expression from the GSTP1 promoter in vivo. GSTP1 expression was moderately but significantly (P = 0.01) reduced after siRNA-mediated knockdown of c-Myb. Our results indicate that haplotype structure of a promoter is important for the extent of DNA methylation. [Cancer Res 2008;68(14):5562–71]
- Published
- 2008
11. Heterogeneous DNA Methylation Patterns in the GSTP1 Promoter Lead to Discordant Results between Assay Technologies and Impede Its Implementation as Epigenetic Biomarkers in Breast Cancer
- Author
-
Jo Anders Rønneberg, Jörg Tost, Vessela N. Kristensen, and Grethe I. Grenaker Alnæs
- Subjects
lcsh:QH426-470 ,Bisulfite sequencing ,Biology ,GSTP1 ,Article ,breast cancer ,Genetics ,medicine ,Methylated DNA immunoprecipitation ,Genetics (clinical) ,mass spectrometry ,DNA methylation ,MSP ,Cancer ,Methylation ,medicine.disease ,MethyLight ,lcsh:Genetics ,Biomarker ,pyrosequencing ,CpG site ,Cancer research ,method ,Illumina Methylation Assay ,biomarker ,heterogeneity - Abstract
Altered DNA methylation patterns are found in many diseases, particularly in cancer, where the analysis of DNA methylation holds the promise to provide diagnostic, prognostic and predictive information of great clinical value. Methylation of the promoter-associated CpG island of GSTP1 occurs in many hormone-sensitive cancers, has been shown to be a biomarker for the early detection of cancerous lesions and has been associated with important clinical parameters, such as survival and response to treatment. In the current manuscript, we assessed the performance of several widely-used sodium bisulfite conversion-dependent methods (methylation-specific PCR, MethyLight, pyrosequencing and MALDI mass-spectrometry) for the analysis of DNA methylation patterns in the GSTP1 promoter. We observed large discordances between the results obtained by the different technologies. Cloning and sequencing of the investigated region resolved single-molecule DNA methylation patterns and identified heterogeneous DNA methylation patterns as the underlying cause of the differences. Heterogeneous DNA methylation patterns in the GSTP1 promoter constitute a major obstacle to the implementation of DNA methylation-based analysis of GSTP1 and might explain some of the contradictory findings in the analysis of the significance of GSTP1 promoter methylation in breast cancer.
- Published
- 2015
- Full Text
- View/download PDF
12. Correction: miRNA-mRNA Integrated Analysis Reveals Roles for miRNAs in Primary Breast Tumors
- Author
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Kristine Kleivi, Hilde Johnsen, Jo Anders Rønneberg, Espen Enerly, Suvi-Katri Leivonen, Miriam Ragle Aure, Bjørn Naume, Olli Kallioniemi, Israel Steinfeld, Einar Andreas Rødland, Zohar Yakhini, Merja Perälä, Hege G. Russnes, Anne Lise Børresen-Dale, Rami Mäkelä, Roy Navon, and Vessela N. Kristensen
- Subjects
0303 health sciences ,Multidisciplinary ,Science ,media_common.quotation_subject ,lcsh:R ,Correction ,lcsh:Medicine ,02 engineering and technology ,Computational biology ,Biology ,021001 nanoscience & nanotechnology ,Legend ,Bioinformatics ,03 medical and health sciences ,microRNA ,Medicine ,lcsh:Q ,0210 nano-technology ,lcsh:Science ,030304 developmental biology ,media_common - Abstract
Supporting Information Figures S6 and S7 were incorrectly switched. The image currently appearing as Figure S6 corresponds to the title and legend for Figure S7, and the image currently appearing as Figure S7 corresponds to the title and legend for Figure S6. The titles and legends themselves are in correct order.
- Published
- 2013
13. miRNA-mRNA integrated analysis reveals roles for miRNAs in primary breast tumors
- Author
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Miriam Ragle Aure, Israel Steinfeld, Einar Andreas Rødland, Suvi-Katri Leivonen, Olli Kallioniemi, Rami Mäkelä, Bjørn Naume, Zohar Yakhini, Vessela N. Kristensen, Roy Navon, Hilde Johnsen, Jo Anders Rønneberg, Merja Perälä, Anne Lise Børresen-Dale, Kristine Kleivi, Hege G. Russnes, Espen Enerly, and Institute for Molecular Medicine Finland
- Subjects
Microarrays ,Gene Expression ,Validation Studies as Topic ,Bioinformatics ,0302 clinical medicine ,MOLECULAR SUBTYPES ,Basic Cancer Research ,Regulation of gene expression ,0303 health sciences ,Multidisciplinary ,microRNA ,Genomics ,3. Good health ,MIR-150 ,Gene Expression Regulation, Neoplastic ,HUMAN MICRORNAS ,DIFFERENTIATION ,Oncology ,030220 oncology & carcinogenesis ,Medicine ,Female ,DNA microarray ,Research Article ,Macromolecular Substances ,BONE-MARROW ,Systems biology ,Science ,education ,Breast Neoplasms ,Computational biology ,Biology ,Models, Biological ,CLASSIFICATION ,C-MYB ,Molecular Genetics ,03 medical and health sciences ,Breast cancer ,breast cancer ,SDG 3 - Good Health and Well-being ,TARGETS ,miR-150 ,Cell Line, Tumor ,medicine ,Genetics ,Cancer Genetics ,Cancer Detection and Diagnosis ,Humans ,cancer ,Gene Regulation ,RNA, Messenger ,030304 developmental biology ,Microarray analysis techniques ,Gene Expression Profiling ,Carcinoma ,CANCER CELL-PROLIFERATION ,Computational Biology ,medicine.disease ,Microarray Analysis ,High-Throughput Screening Assays ,Gene expression profiling ,Systems Integration ,MicroRNAs ,GENE-EXPRESSION PROFILES ,Mutation ,3111 Biomedicine ,Tumor Suppressor Protein p53 ,Genome Expression Analysis - Abstract
IntroductionFew studies have performed expression profiling of both miRNA and mRNA from the same primary breast carcinomas. In this study we present and analyze data derived from expression profiling of 799 miRNAs in 101 primary human breast tumors, along with genome-wide mRNA profiles and extensive clinical information.MethodsWe investigate the relationship between these molecular components, in terms of their correlation with each other and with clinical characteristics. We use a systems biology approach to examine the correlative relationship between miRNA and mRNAs using statistical enrichment methods.ResultsWe identify statistical significant differential expression of miRNAs between molecular intrinsic subtypes, and between samples with different levels of proliferation. Specifically, we point to miRNAs significantly associated with TP53 and ER status. We also show that several cellular processes, such as proliferation, cell adhesion and immune response, are strongly associated with certain miRNAs. We validate the role of miRNAs in regulating proliferation using high-throughput lysate-microarrays on cell lines and point to potential drivers of this process.ConclusionThis study provides a comprehensive dataset as well as methods and system-level results that jointly form a basis for further work on understanding the role of miRNA in primary breast cancer.
- Published
- 2011
14. The epigenetics of breast cancer
- Author
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Jo Anders Rønneberg, Jörg Tost, Jovana Jovanovic, and Vessela N. Kristensen
- Subjects
Cancer Research ,Epigenetic regulation of neurogenesis ,Epigenetic code ,Reviews ,Breast Neoplasms ,Biology ,Epigenesis, Genetic ,Histones ,Epigenetics of physical exercise ,Genetics ,Biomarkers, Tumor ,Humans ,Epigenetics ,Cancer epigenetics ,RNA-Directed DNA Methylation ,DNA Modification Methylases ,Epigenomics ,Molecular Structure ,General Medicine ,DNA ,DNA Methylation ,Prognosis ,Chromatin ,Gene Expression Regulation, Neoplastic ,MicroRNAs ,Oncology ,Receptors, Estrogen ,DNA methylation ,Molecular Medicine ,Female - Abstract
Epigenetic changes can be defined as stable molecular alterations of a cellular phenotype such as the gene expression profile of a cell that are heritable during somatic cell divisions (and sometimes germ line transmissions) but do not involve changes of the DNA sequence itself. Epigenetic phenomena are mediated by several molecular mechanisms comprising histone modifications, polycomb/trithorax protein complexes, small non-coding or antisense RNAs and DNA methylation. These different modifications are closely interconnected. Epigenetic regulation is critical in normal growth and development and closely conditions the transcriptional potential of genes. Epigenetic mechanisms convey genomic adaption to an environment thereby ultimately contributing towards given phenotype. In this review we will describe the various aspects of epigenetics and in particular DNA methylation in breast carcinogenesis and their potential application for diagnosis, prognosis and treatment decision.
- Published
- 2010
15. Frequent aberrant DNA methylation of ABCB1, FOXC1, PPP2R2B and PTEN in ductal carcinoma in situ and early invasive breast cancer
- Author
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Vessela N. Kristensen, Hiroko K. Solvang, Anne Lise Børresen-Dale, Jo Anders Rønneberg, Florence Busato, Jovana Jovanovic, Jörg Tost, Therese Sørlie, Ida Rashida Khan Bukholm, Johan Botling, Fredrik Wärnberg, and Aslaug Aa Muggerud
- Subjects
Pathology ,medicine.medical_specialty ,ATP Binding Cassette Transporter, Subfamily B ,Breast Neoplasms ,Nerve Tissue Proteins ,Biology ,MLH1 ,Breast cancer ,Research article ,medicine ,Carcinoma ,Humans ,PTEN ,Neoplasm Invasiveness ,ATP Binding Cassette Transporter, Subfamily B, Member 1 ,Protein Phosphatase 2 ,Epigenetics ,Promoter Regions, Genetic ,skin and connective tissue diseases ,neoplasms ,Medicine(all) ,PTEN Phosphohydrolase ,Forkhead Transcription Factors ,Methylation ,DNA Methylation ,Ductal carcinoma ,Genes, p53 ,medicine.disease ,eye diseases ,body regions ,Carcinoma, Intraductal, Noninfiltrating ,Mutation ,DNA methylation ,Cancer research ,biology.protein ,CpG Islands ,Female ,sense organs - Abstract
Introduction Ductal carcinoma in situ (DCIS) is a non-invasive lesion of the breast that is frequently detected by mammography and subsequently removed by surgery. However, it is estimated that about half of the detected lesions would never have progressed into invasive cancer. Identifying DCIS and invasive cancer specific epigenetic lesions and understanding how these epigenetic changes are involved in triggering tumour progression is important for a better understanding of which lesions are at risk of becoming invasive. Methods Quantitative DNA methylation analysis of ABCB1, CDKN2A/p16 INK4a , ESR1, FOXC1, GSTP1, IGF2, MGMT, MLH1, PPP2R2B, PTEN and RASSF1A was performed by pyrosequencing in a series of 27 pure DCIS, 28 small invasive ductal carcinomas (IDCs), 34 IDCs with a DCIS component and 5 normal breast tissue samples. FOXC1, ABCB1, PPP2R2B and PTEN were analyzed in 23 additional normal breast tissue samples. Real-Time PCR expression analysis was performed for FOXC1. Results Aberrant DNA methylation was observed in all three diagnosis groups for the following genes: ABCB1, FOXC1, GSTP1, MGMT, MLH1, PPP2R2B, PTEN and RASSF1A. For most of these genes, methylation was already present at the DCIS level with the same frequency as within IDCs. For FOXC1 significant differences in methylation levels were observed between normal breast tissue and invasive tumours (P < 0.001). The average DNA methylation levels were significantly higher in the pure IDCs and IDCs with DCIS compared to pure DCIS (P = 0.007 and P = 0.001, respectively). Real-time PCR analysis of FOXC1 expression from 25 DCIS, 23 IDCs and 28 normal tissue samples showed lower gene expression levels of FOXC1 in both methylated and unmethylated tumours compared to normal tissue (P < 0.001). DNA methylation levels of FOXC1, GSTP1, ABCB1 and RASSF1A were higher in oestrogen receptor (ER) positive vs. ER negative tumours; whereas methylation levels of FOXC1, ABCB1, PPP2R2B and PTEN were lower in tumours with a TP53 mutation. Conclusions Quantitative methylation analysis identified ABCB1, FOXC1, PPP2R2B and PTEN as novel genes to be methylated in DCIS. In particular, FOXC1 showed a significant increase in the methylation frequency in invasive tumours. Low FOXC1 gene expression in both methylated and unmethylated DCIS and IDCs indicates that the loss of its expression is an early event during breast cancer progression.
- Published
- 2010
16. DNA methylation profiling in doxorubicin treated primary locally advanced breast tumours identifies novel genes associated with survival and treatment response
- Author
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Ida R. K. Bukholm, Vessela N. Kristensen, Hiroko K. Solvang, Emelyne Dejeux, Per Eystein Lønning, Jo Anders Rønneberg, Jörg Tost, Anne Lise Børresen-Dale, Stephanie Geisler, Turid Aas, and Ivo Gut
- Subjects
Adult ,Cancer Research ,Gene Expression ,Antineoplastic Agents ,Breast Neoplasms ,Kaplan-Meier Estimate ,Biology ,lcsh:RC254-282 ,GSTP1 ,Breast cancer ,CDKN2A ,medicine ,Humans ,Epigenetics ,skin and connective tissue diseases ,Promoter Regions, Genetic ,Medisinske Fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710::Medisinsk genetikk: 714 [VDP] ,Aged ,Oligonucleotide Array Sequence Analysis ,Aged, 80 and over ,Gene Expression Profiling ,Research ,Cancer ,Promoter ,Methylation ,DNA Methylation ,Middle Aged ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Oncology ,Doxorubicin ,Drug Resistance, Neoplasm ,DNA methylation ,Cancer research ,Molecular Medicine ,Female - Abstract
Background Breast cancer is the most frequent cancer in women and consists of a heterogeneous collection of diseases with distinct histopathological, genetic and epigenetic characteristics. In this study, we aimed to identify DNA methylation based biomarkers to distinguish patients with locally advanced breast cancer who may benefit from neoadjuvant doxorubicin treatment. Results We investigated quantitatively the methylation patterns in the promoter regions of 14 genes (ABCB1, ATM, BRCA1, CDH3, CDKN2A, CXCR4, ESR1, FBXW7, FOXC 1, GSTP1, IGF2, HMLH1, PPP2R2B, and PTEN) in 75 well-described pre-treatment samples from locally advanced breast cancer and correlated the results to the available clinical and molecular parameters. Six normal breast tissues were used as controls and 163 unselected breast cancer cases were used to validate associations with histopathological and clinical parameters. Aberrant methylation was detected in 9 out of the 14 genes including the discovery of methylation at the FOXC1 promoter. Absence of methylation at the ABCB1 promoter correlated with progressive disease during doxorubicin treatment. Most importantly, the DNA methylation status at the promoters of GSTP1, FOXC1 and ABCB1 correlated with survival, whereby the combination of methylated genes improved the subdivision with respect to the survival of the patients. In multivariate analysis GSTP1 and FOXC1 methylation status proved to be independent prognostic markers associated with survival. Conclusions Quantitative DNA methylation profiling is a powerful tool to identify molecular changes associated with specific phenotypes. Methylation at the ABCB1 or GSTP1 promoter improved overall survival probably due to prolonged availability and activity of the drug in the cell while FOXC1 methylation might be a protective factor against tumour invasiveness. FOXC1 proved to be general prognostic factor, while ABCB1 and GSTP1 might be predictive factors for the response to and efficacy of doxorubicin treatment. Pharmacoepigenetic effects such as the reported associations in this study provide molecular explanations for differential responses to chemotherapy and it might prove valuable to take the methylation status of selected genes into account for patient management and treatment decisions.
- Published
- 2009
17. 875 Methylation and mRNA expression profile provide supplementary information about the molecular characteristics of breast cancer tumours with clinical implications
- Author
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Hege Edvardsen, H.K. Solvang, J. Jovanovic, Bjørn Naume, V.N. Kristensen, A.L. Børresen-Dale, Jo Anders Rønneberg, Jörg Tost, G.I. Grenaker Alnæs, and T. Fleischer
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Breast cancer ,business.industry ,Internal medicine ,Mrna expression ,medicine ,Methylation ,medicine.disease ,business - Published
- 2010
18. Genetic polymorphisms in the 5' flanking region of glutathione S-transferase P1 affect promoter methylation
- Author
-
GI Grenaker-Alnæs, I Gut, T Sørlie, A-L Børresen-Dale, V.N. Kristensen, Tom Kristensen, Jo Anders Rønneberg, and Jörg Tost
- Subjects
biology ,5' flanking region ,Promoter ,Methylation ,urologic and male genital diseases ,Chromatin remodeling ,GSTP1 ,Histone ,CpG site ,DNA methylation ,Poster Presentation ,Cancer research ,biology.protein ,neoplasms - Abstract
Glutathione-S-transferase P1 (GSTP1) is involved in thiol-mediated detoxification and breakdown of reactive oxygen species created by anticancer drug exposure. GSTP1 is also an inhibitor of c-Jun N-terminal kinase 1, a kinase involved in stress response, apoptosis and cellular proliferation. Hypermethylation of the GSTP1 promoter has been associated with gene silencing in prostate cancer, kidney cancer, and breast cancer, among others. Although frequently described, the mechanism underlying promoter hypermethylation of the GSTP1 gene is poorly understood. It has been reported that an ATAAA repeat of the GSTP1 promoter separates methylated from unmethylated CpGs in normal prostate tissue [1]. These separate methylation domains are lost in prostate cancer, and methylation extends throughout the whole promoter region. It has been proposed that hypermethylation of GSTP1 requires a combination of gene silencing and random seeds of methylation in prostate cancer cells, and that these combinatorial effects lead to histone deacetylation and subsequent chromatin remodeling [2]. To further elucidate the mechanisms underlying the hypermethylation of the GSTP1 promoter, we genotyped the (ATAAA) repeat and the linked SNPs in positions -354, -288, -287 and -282 in the GSTP1 promoter and we performed methylation analysis using mass spectrometry in tumor DNA from 82 breast cancer patients. The role of the different allelic variants on methylation status of the GSTP1 promoter and expression levels was assessed. We quantitatively determined the methylation status of six CpGs spanning the transcription start site of the GSTP1 promoter: -22, +8, +14, +38, +47 and +55. The average percentage methylation for each individual CpG for the 82 tumor samples analyzed was 16.9%, 30.3%, 18.2%, 21.2%, 18.6% and 8.1%, respectively. The average percentage methylation for all CpGs in all tumor samples was 19%. There was a correlation between the degree of methylation of the individual CpGs and their neighboring CpGs (P < 0.001). When correlating the extent of methylation to the mRNA levels previously assessed by whole genome gene-expression profiling of the same tumors, a significant inverse correlation was observed (P < 0.01). The methylation status of the three CpGs closest to the transcriptional start site was more highly associated with the level of GSTP1 mRNA expression than the CpGs further downstream of the +1 site. Furthermore, we observed differences in the degree of GSTP1 promoter methylation between the different tumor subclasses defined by whole-genome microarray analysis [3]. The methylation of the GSTP1 promoter was significantly lower in the basal subtype compared with the luminal subtype, which corresponded to elevated GSTP1 mRNA levels in the basal subtypes [4]. We further analyzed the impact of the most frequent haplotype structure of the GSTP1 promoter in relation to the extent of methylation, and a correlation was observed (P = 0.003) suggesting that haplotype structures can affect de novo methylation of adjacent sequences.
- Published
- 2005
19. Heterogeneous DNA Methylation Patterns in the GSTP1 Promoter Lead to Discordant Results between Assay Technologies and Impede Its Implementation as Epigenetic Biomarkers in Breast Cancer
- Author
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Grethe I. Grenaker Alnaes, Jo Anders Ronneberg, Vessela N. Kristensen, and Jörg Tost
- Subjects
DNA methylation ,breast cancer ,GSTP1 ,biomarker ,heterogeneity ,method ,MethyLight ,MSP ,pyrosequencing ,mass spectrometry ,Genetics ,QH426-470 - Abstract
Altered DNA methylation patterns are found in many diseases, particularly in cancer, where the analysis of DNA methylation holds the promise to provide diagnostic, prognostic and predictive information of great clinical value. Methylation of the promoter-associated CpG island of GSTP1 occurs in many hormone-sensitive cancers, has been shown to be a biomarker for the early detection of cancerous lesions and has been associated with important clinical parameters, such as survival and response to treatment. In the current manuscript, we assessed the performance of several widely-used sodium bisulfite conversion-dependent methods (methylation-specific PCR, MethyLight, pyrosequencing and MALDI mass-spectrometry) for the analysis of DNA methylation patterns in the GSTP1 promoter. We observed large discordances between the results obtained by the different technologies. Cloning and sequencing of the investigated region resolved single-molecule DNA methylation patterns and identified heterogeneous DNA methylation patterns as the underlying cause of the differences. Heterogeneous DNA methylation patterns in the GSTP1 promoter constitute a major obstacle to the implementation of DNA methylation-based analysis of GSTP1 and might explain some of the contradictory findings in the analysis of the significance of GSTP1 promoter methylation in breast cancer.
- Published
- 2015
- Full Text
- View/download PDF
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