14 results on '"Jovana Klajic"'
Search Results
2. Data from DNA Methylation Status of Key Cell-Cycle Regulators Such as CDKNA2/p16 and CCNA1 Correlates with Treatment Response to Doxorubicin and 5-Fluorouracil in Locally Advanced Breast Tumors
- Author
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Vessela N. Kristensen, Jörg Tost, Per Eystein Lønning, Anne-Lise Børresen-Dale, Ida Bukholm, Thomas Fleischer, Nizar Touleimat, Hege Edvardsen, Florence Busato, and Jovana Klajic
- Abstract
Purpose: To explore alterations in gene promoter methylation as a potential cause of acquired drug resistance to doxorubicin or combined treatment with 5-fluorouracil and mitomycin C in human breast cancers.Experimental Design: Paired tumor samples from locally advanced breast cancer patients treated with doxorubicin and 5-fluorouracil-mitomycin C were used in the genome-wide DNA methylation analysis as discovery cohort. An enlarged cohort from the same two prospective studies as those in the discovery cohort was used as a validation set in pyrosequencing analysis.Results: A total of 469 genes were differentially methylated after treatment with doxorubicin and revealed a significant association with canonical pathways enriched for immune cell response and cell-cycle regulating genes including CDKN2A, CCND2, CCNA1, which were also associated to treatment response. Treatment with FUMI resulted in 343 differentially methylated genes representing canonical pathways such as retinoate biosynthesis, gαi signaling, and LXR/RXR activation. Despite the clearly different genes and pathways involved in the metabolism and therapeutic effect of both drugs, 46 genes were differentially methylated before and after treatment with both doxorubicin and FUMI. DNA methylation profiles in genes such as BRCA1, FOXC1, and IGFBP3, and most notably repetitive elements like ALU and LINE1, were associated with TP53 mutations status.Conclusion: We identified and validated key cell-cycle regulators differentially methylated before and after neoadjuvant chemotherapy such as CDKN2A and CCNA1 and reported that methylation patterns of these genes may be potential predictive markers to anthracycline/mitomycine sensitivity. Clin Cancer Res; 20(24); 6357–66. ©2014 AACR.
- Published
- 2023
3. Supplementary Figure 1 from DNA Methylation Status of Key Cell-Cycle Regulators Such as CDKNA2/p16 and CCNA1 Correlates with Treatment Response to Doxorubicin and 5-Fluorouracil in Locally Advanced Breast Tumors
- Author
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Vessela N. Kristensen, Jörg Tost, Per Eystein Lønning, Anne-Lise Børresen-Dale, Ida Bukholm, Thomas Fleischer, Nizar Touleimat, Hege Edvardsen, Florence Busato, and Jovana Klajic
- Abstract
Supplementary Figure 1. Canonical pathway:Communication between Innate and Adaptive Immune Cells
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- 2023
4. Supplementary Table 1-6 from DNA Methylation Status of Key Cell-Cycle Regulators Such as CDKNA2/p16 and CCNA1 Correlates with Treatment Response to Doxorubicin and 5-Fluorouracil in Locally Advanced Breast Tumors
- Author
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Vessela N. Kristensen, Jörg Tost, Per Eystein Lønning, Anne-Lise Børresen-Dale, Ida Bukholm, Thomas Fleischer, Nizar Touleimat, Hege Edvardsen, Florence Busato, and Jovana Klajic
- Abstract
Supplementary Table 1-6. Supplementary Table 1: Differentially methylated genes and functions of the genes before/after treatment with doxorubicin and FUMI Supplementary Table 2: Ingenuity Pathway analysis Supplementary Table 3: List and function of the 46 differentially methylated genes Supplementary Table 4: List of the 333 differentially methylated genes Supplementary Table 5: Ingenuity Pathway analysis of the 333 differentially methylated genes Supplementary Table 6: Associations between methylation status and TP53 mutation status
- Published
- 2023
5. Supplementary Figure 2 from DNA Methylation Status of Key Cell-Cycle Regulators Such as CDKNA2/p16 and CCNA1 Correlates with Treatment Response to Doxorubicin and 5-Fluorouracil in Locally Advanced Breast Tumors
- Author
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Vessela N. Kristensen, Jörg Tost, Per Eystein Lønning, Anne-Lise Børresen-Dale, Ida Bukholm, Thomas Fleischer, Nizar Touleimat, Hege Edvardsen, Florence Busato, and Jovana Klajic
- Abstract
Supplementary Figure 2. Canonical pathway:Gαi Signalling
- Published
- 2023
6. Development of high‑resolution melting analysis for ABCB1 promoter methylation: Clinical consequences in breast and ovarian carcinoma
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Lukas Rob, Katerina Elsnerova, Vessela N. Kristensen, Marcela Mrhalova, Grethe I. Grenaker Alnæs, Jovana Klajic, Veronika Brynychova, Petr Skapa, Radka Vaclavikova, Jörg Tost, Roman Kodet, and Pavel Soucek
- Subjects
0301 basic medicine ,Cancer Research ,ATP Binding Cassette Transporter, Subfamily B ,Breast Neoplasms ,Nucleic Acid Denaturation ,Polymerase Chain Reaction ,High Resolution Melt ,Epigenesis, Genetic ,03 medical and health sciences ,0302 clinical medicine ,Ovarian carcinoma ,Biomarkers, Tumor ,Carcinoma ,Humans ,Medicine ,Neoplasm Invasiveness ,Epigenetics ,Promoter Regions, Genetic ,Retrospective Studies ,Ovarian Neoplasms ,Regulation of gene expression ,business.industry ,Carcinoma, Ductal, Breast ,Cancer ,General Medicine ,Methylation ,DNA Methylation ,Prognosis ,medicine.disease ,Cystadenocarcinoma, Serous ,Gene Expression Regulation, Neoplastic ,Survival Rate ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,DNA methylation ,Cancer research ,Female ,business ,Follow-Up Studies - Abstract
Multidrug resistance to anticancer drugs, which is often associated with enhanced expression of the ATP‑binding cassette (ABC) transporter P‑glycoprotein (encoded by the ABCB1 gene) may limit the effects of cancer therapy. Epigenetic regulation of ABCB1 expression may thus have a clinical impact. A detailed assessment of ABCB1 promoter methylation is of importance for predicting therapy outcome and prognosis. Thus, validated methods for the analysis of ABCB1 promoter methylation are urgently required. In the present study, high‑resolution melting (HRM) analysis of the CpG island regions covering the distal promoter of the ABCB1 gene was developed and compared with pyrosequencing. In addition, the clinical effects of the methylation status of the ABCB1 promoter were analyzed in patients with breast and ovarian carcinoma prior and subsequent to chemotherapy treatment. HRM analysis of ABCB1 methylation correlated with the results of pyrosequencing (P=0.001) demonstrating its analytical validity and utility. Hypermethylation of the analyzed ABCB1 promoter region was significantly correlated with low levels of the ABCB1 transcript in tumors from a subset of patients with breast and ovarian carcinoma prior to chemotherapy but not following treatment. Finally, high ABCB1 transcript levels were observed in tumors of patients with short progression‑free survival prior to chemotherapy. Our data suggest the existence of functional epigenetic changes in the ABCB1 gene with prognostic value in tumor tissues of patients with breast and ovarian carcinoma. The clinical importance of such changes should be further evaluated.
- Published
- 2019
7. List of Contributors
- Author
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Tomi Akinyemiju, Samuel Anti, Ritikraj Arya, Marine Baptissart, Raffaela Barbano, Timothy M. Barrow, Teena Bhatla, Kartz Bibb, William L. Carroll, Fabio Coppedè, Jovana Klajic, Vessela Kristensen, Sanjay Kumar, Bernard Kwabi-Addo, Angela Lopomo, Pillai Pallavi Madhusoodhan, Emmanuelle Martinot, Shabana S. Meyering, Manoj K. Mishra, Paola Parrella, Barbara Pasculli, Sabita N. Saldanha, Brenda C. Salumbides, Lauriane Sédes, Rajesh Singh, Shriti Singh, Lula Smith, David H. Volle, and Natalie White
- Published
- 2018
8. Epigenetics of Breast Cancer
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Vessela N. Kristensen and Jovana Klajic
- Subjects
0301 basic medicine ,biology ,Cancer ,medicine.disease ,medicine.disease_cause ,Chromatin remodeling ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Histone ,Breast cancer ,030220 oncology & carcinogenesis ,DNA methylation ,biology.protein ,medicine ,Cancer research ,Cancer epigenetics ,Epigenetics ,skin and connective tissue diseases ,Carcinogenesis - 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. The main epigenetic mechanisms include DNA methylation, histone modifications, chromatin remodeling, and RNA-associated silencing. These different modifications are closely interconnected. Despite the availability of new chemotherapeutic agents and progress in prevention and surveillance, breast cancer is still the most common cancer affecting women in developed countries. Clinically, breast cancer is a heterogeneous disease, and in addition to genetic abnormalities, epigenetic alterations may contribute to breast carcinogenesis and tumor growth. In this chapter 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
- 2018
9. DNA methylation signature (SAM40) identifies subgroups of the Luminal A breast cancer samples with distinct survival
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Thomas Fleischer, Per Eystein Lønning, Joerg Tost, Riku Louhimo, Arne V. Pladsen, Bjørn Naume, Anne Lise Børresen-Dale, Margit Riis, Grethe I. Grenaker Alnæs, Ann Rita Halvorsen, Lars Ottestad, Jovana Klajic, Sampsa Hautaniemi, Åslaug Helland, Marko Laakso, Miriam Ragle Aure, Nizar Touleimat, Vessela N. Kristensen, Research Programs Unit, Genome-Scale Biology (GSB) Research Program, Sampsa Hautaniemi / Principal Investigator, Bioinformatics, Informatique, Biologie Intégrative et Systèmes Complexes (IBISC), Université d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS), Department of Oncology, The Norwegian Radium Hospital, Akershus University Hospital [Lørenskog], University of Oslo (UiO), Laboratory for Epigenetics and Environment, and Centre National de Genotypage
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Epigenomics ,0301 basic medicine ,Pathology ,PROGNOSIS ,Adjuvant chemotherapy ,[SDV]Life Sciences [q-bio] ,Gene Dosage ,Kaplan-Meier Estimate ,Disease ,Epigenesis, Genetic ,NORMALIZATION ,0302 clinical medicine ,[STAT.ML]Statistics [stat]/Machine Learning [stat.ML] ,MOLECULAR SUBTYPES ,Cluster Analysis ,ComputingMilieux_MISCELLANEOUS ,RISK ,[STAT.AP]Statistics [stat]/Applications [stat.AP] ,DNA methylation ,University hospital ,[SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM] ,TUMORS ,3. Good health ,Gene Expression Regulation, Neoplastic ,[STAT]Statistics [stat] ,Luminal A ,Oncology ,classification ,030220 oncology & carcinogenesis ,language ,Female ,Research Paper ,medicine.medical_specialty ,DOXORUBICIN ,3122 Cancers ,Clinical science ,Breast Neoplasms ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Norwegian ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,03 medical and health sciences ,Breast cancer ,breast cancer ,Biomarkers, Tumor ,medicine ,Humans ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,RECURRENCE ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,business.industry ,Gene Expression Profiling ,General surgery ,Cancer ,Luminal a ,medicine.disease ,language.human_language ,030104 developmental biology ,GENE-EXPRESSION PROFILES ,DENSITY ,PATTERNS ,1182 Biochemistry, cell and molecular biology ,Transcriptome ,business ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology - Abstract
// Thomas Fleischer 1, * , Jovana Klajic 1, 2, * , Miriam Ragle Aure 1 , Riku Louhimo 3 , Arne V. Pladsen 1 , Lars Ottestad 1 , Nizar Touleimat 4 , Marko Laakso 3 , Ann Rita Halvorsen 1 , Grethe I. Grenaker Alnaes 1 , Margit L.H. Riis 2, 5, 6 , Aslaug Helland 1, 7 , Sampsa Hautaniemi 3 , Per Eystein Lonning 8, 9 , Bjorn Naume 10 , Anne-Lise Borresen-Dale 1 , Jorg Tost 4 , Vessela N. Kristensen 1, 2 1 Department of Cancer Genetics, Institute for Cancer Research, OUS Radiumhospitalet, Oslo, Norway 2 Department of Clinical Molecular Biology and Laboratory Science (EpiGen), Akershus University hospital, Division of Medicine, Lorenskog, Norway 3 Systems Biology Laboratory, Institute of Biomedicine and Genome-Scale Biology Research Program, University of Helsinki, Finland 4 Laboratory for Epigenetics and Environment, Centre National de Genotypage, CEA – Institut de Genomique, France 5 Department of Surgery, Akershus University Hospital, Lorenskog, Norway 6 Deptartment of Breast and Endocrine Surgery, Oslo University Hospital, Ulleval, Norway 7 Department of Oncology, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway 8 Section of Oncology, Institute of Clinical Science, University of Bergen, Bergen, Norway 9 Department of Oncology, Haukeland University Hospital, Bergen, Norway 10 Cancer Clinic, Oslo University Hospital Radiumhospitalet, Oslo, Norway * These authors contributed equally to this work Correspondence to: Vessela N. Kristensen, email: v.n.kristensen@medisin.uio.no Keywords: breast cancer, Luminal A, DNA methylation, classification, prognosis Received: June 21, 2016 Accepted: November 07, 2016 Published: November 30, 2016 ABSTRACT Breast cancer patients with Luminal A disease generally have a good prognosis, but among this patient group are patients with good prognosis that are currently overtreated with adjuvant chemotherapy, and also patients that have a bad prognosis and should be given more aggressive treatment. There is no available method for subclassification of this patient group. Here we present a DNA methylation signature (SAM40) that segregates Luminal A patients based on prognosis, and identify one good prognosis group and one bad prognosis group. The prognostic impact of SAM40 was validated in four independent patient cohorts. Being able to subdivide the Luminal A patients may give the two-sided benefit of identifying one subgroup that may benefit from a more aggressive treatment than what is given today, and importantly, identifying a subgroup that may benefit from less treatment.
- Published
- 2017
10. GFRA3 promoter methylation may be associated with decreased postoperative survival in gastric cancer
- Author
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Gustav Peter Blom, Vessela N. Kristensen, Qin Ying Esbensen, Ida Rashida Khan Bukholm, Jovana Klajic, Jörg Tost, Lars Lohne Eftang, and Geir Bukholm
- Subjects
Male ,0301 basic medicine ,Pathology ,medicine.medical_specialty ,Cancer Research ,Glial Cell Line-Derived Neurotrophic Factor Receptors ,Survival ,GFRA3 ,Biology ,Disease-Free Survival ,Transcriptome ,03 medical and health sciences ,0302 clinical medicine ,Stomach Neoplasms ,Gene expression ,Biomarkers, Tumor ,medicine ,Genetics ,Humans ,Postoperative Period ,Epigenetics ,Promoter Regions, Genetic ,Gene ,Aged ,DNA methylation ,Cancer ,Promoter ,Methylation ,Middle Aged ,Prognosis ,medicine.disease ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Oncology ,Lymphatic Metastasis ,030220 oncology & carcinogenesis ,Cancer research ,CpG Islands ,Female ,Gastric cancer ,Research Article - Abstract
Background A large number of epigenetic alterations has been found to be implicated in the etiology of gastric cancer. We have studied the DNA methylation status of 27 500 gene promoter regions in 24 gastric adenocarcinomas from a Norwegian cohort, and aimed at identifying the hypermethylated regions. We have compared our findings to the gene expression in the same tissue, and linked our results to prognosis and survival. Methods Biopsies from gastric adenocarcinomas and adjacent normal gastric mucosa were obtained from 24 patients following surgical resection of the tumor. Genome-wide DNA methylation profiling of the tumor and matched non-cancerous mucosa was performed. The results were compared to whole transcriptome cDNA microarray analysis of the same material. Results Most of the gene promoter regions in both types of tissue showed a low degree of methylation, however there was a small, but significant hypermethylation of the tumors. Hierarchical clustering showed separate grouping of the tumor and normal tissue. Hypermethylation of the promoter region of the GFRA3 gene showed a strong correlation to post-operative survival and several of the clinicopathological parameters, however no difference was found between the two main histological types of gastric cancer. There was only a modest correlation between the DNA methylation status and gene expression. Conclusions The different DNA methylation clusters of the tumors and normal tissue indicate that aberrant DNA methylation is a distinct feature of gastric cancer, although there is little difference in the overall, and low, methylation levels between the two tissue types. The GFRA3 promoter region showed marked hypermethylation in almost all tumors, and its correlation with survival and other clinicopathological parameters may have important prognostic significance.
- Published
- 2016
11. DNA Methylation Status of Key Cell-Cycle Regulators Such as CDKNA2/p16 and CCNA1 Correlates with Treatment Response to Doxorubicin and 5-Fluorouracil in Locally Advanced Breast Tumors
- Author
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Anne Lise Børresen-Dale, Florence Busato, Ida R. K. Bukholm, Jörg Tost, Nizar Touleimat, Hege Edvardsen, Vessela N. Kristensen, Jovana Klajic, Thomas Fleischer, Per Eystein Lønning, and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)
- Subjects
Cancer Research ,Anthracycline ,[SDV]Life Sciences [q-bio] ,Breast Neoplasms ,Cell Cycle Proteins ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,Biology ,Cohort Studies ,[STAT.ML]Statistics [stat]/Machine Learning [stat.ML] ,CDKN2A ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Doxorubicin ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Promoter Regions, Genetic ,Cyclin-Dependent Kinase Inhibitor p16 ,ComputingMilieux_MISCELLANEOUS ,Neoplasm Staging ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,Gene Expression Profiling ,Cancer ,Reproducibility of Results ,Promoter ,Methylation ,Cell cycle ,DNA Methylation ,medicine.disease ,Prognosis ,[SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM] ,[STAT]Statistics [stat] ,Treatment Outcome ,Oncology ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,DNA methylation ,Mutation ,Cancer research ,Female ,Cyclin A1 ,Fluorouracil ,Tumor Suppressor Protein p53 ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology ,medicine.drug - Abstract
Purpose: To explore alterations in gene promoter methylation as a potential cause of acquired drug resistance to doxorubicin or combined treatment with 5-fluorouracil and mitomycin C in human breast cancers. Experimental Design: Paired tumor samples from locally advanced breast cancer patients treated with doxorubicin and 5-fluorouracil-mitomycin C were used in the genome-wide DNA methylation analysis as discovery cohort. An enlarged cohort from the same two prospective studies as those in the discovery cohort was used as a validation set in pyrosequencing analysis. Results: A total of 469 genes were differentially methylated after treatment with doxorubicin and revealed a significant association with canonical pathways enriched for immune cell response and cell-cycle regulating genes including CDKN2A, CCND2, CCNA1, which were also associated to treatment response. Treatment with FUMI resulted in 343 differentially methylated genes representing canonical pathways such as retinoate biosynthesis, gαi signaling, and LXR/RXR activation. Despite the clearly different genes and pathways involved in the metabolism and therapeutic effect of both drugs, 46 genes were differentially methylated before and after treatment with both doxorubicin and FUMI. DNA methylation profiles in genes such as BRCA1, FOXC1, and IGFBP3, and most notably repetitive elements like ALU and LINE1, were associated with TP53 mutations status. Conclusion: We identified and validated key cell-cycle regulators differentially methylated before and after neoadjuvant chemotherapy such as CDKN2A and CCNA1 and reported that methylation patterns of these genes may be potential predictive markers to anthracycline/mitomycine sensitivity. Clin Cancer Res; 20(24); 6357–66. ©2014 AACR.
- Published
- 2014
12. Genome-wide DNA methylation profiles in progression to in situand invasive carcinoma of the breast with impact on gene transcription and prognosis
- Author
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Vessela N. Kristensen, Nizar Touleimat, Anne Lise Børresen-Dale, Åslaug Helland, Arnoldo Frigessi, Vilde D. Haakensen, Jörg Tost, Hege Edvardsen, Margit Riis, Thomas Fleischer, Fredrik Wärnberg, Brock C. Christensen, Bjørn Naume, Kevin C. Johnson, Jovana Klajic, Department of Genetics, Institute of Cancer Research, Oslo University Hospital Radiumhospitalet, Informatique, Biologie Intégrative et Systèmes Complexes (IBISC), Université d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS), Department of Oncology, The Norwegian Radium Hospital, Akershus University Hospital [Lørenskog], University of Oslo (UiO), Laboratory for Epigenetics and Environment, and Centre National de Genotypage
- Subjects
Transcription, Genetic ,[SDV]Life Sciences [q-bio] ,Breast Neoplasms ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,Biology ,medicine.disease_cause ,Epigenesis, Genetic ,Breast cancer ,[STAT.ML]Statistics [stat]/Machine Learning [stat.ML] ,medicine ,Carcinoma ,Humans ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Epigenetics ,skin and connective tissue diseases ,ComputingMilieux_MISCELLANEOUS ,Medicinsk genetik ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,Research ,Carcinoma, Ductal, Breast ,Epigenome ,Methylation ,Ductal carcinoma ,DNA Methylation ,medicine.disease ,Prognosis ,Survival Analysis ,[SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM] ,3. Good health ,Gene Expression Regulation, Neoplastic ,[STAT]Statistics [stat] ,Carcinoma, Intraductal, Noninfiltrating ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,DNA methylation ,Cancer research ,Disease Progression ,CpG Islands ,Female ,Carcinogenesis ,Medical Genetics - Abstract
Background Ductal carcinoma in situ (DCIS) of the breast is a precursor of invasive breast carcinoma. DNA methylation alterations are thought to be an early event in progression of cancer, and may prove valuable as a tool in clinical decision making and for understanding neoplastic development. Results We generate genome-wide DNA methylation profiles of 285 breast tissue samples representing progression of cancer, and validate methylation changes between normal and DCIS in an independent dataset of 15 normal and 40 DCIS samples. We also validate a prognostic signature on 583 breast cancer samples from The Cancer Genome Atlas. Our analysis reveals that DNA methylation profiles of DCIS are radically altered compared to normal breast tissue, involving more than 5,000 genes. Changes between DCIS and invasive breast carcinoma involve around 1,000 genes. In tumors, DNA methylation is associated with gene expression of almost 3,000 genes, including both negative and positive correlations. A prognostic signature based on methylation level of 18 CpGs is associated with survival of breast cancer patients with invasive tumors, as well as with survival of patients with DCIS and mixed lesions of DCIS and invasive breast carcinoma. Conclusions This work demonstrates that changes in the epigenome occur early in the neoplastic progression, provides evidence for the possible utilization of DNA methylation-based markers of progression in the clinic, and highlights the importance of epigenetic changes in carcinogenesis. Electronic supplementary material The online version of this article (doi:10.1186/s13059-014-0435-x) contains supplementary material, which is available to authorized users.
- Published
- 2014
13. Quantitative DNA methylation analyses reveal stage dependent DNA methylation and association to clinico-pathological factors in breast tumors
- Author
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Jovana Klajic, Fredrik Wärnberg, Jörg Tost, Emelyne Dejeux, Anne Lise Børresen-Dale, Vessela N. Kristensen, Hege Edvardsen, Hiroko K. Solvang, Thomas Fleischer, Per Eystein Lønning, and Ida R. K. Bukholm
- Subjects
Stage ,Cancer Research ,Medicin och hälsovetenskap ,Receptor, ErbB-2 ,Breast Neoplasms ,Biology ,Medical and Health Sciences ,Epigenesis, Genetic ,GSTP1 ,Breast cancer ,Surgical oncology ,CDKN2A ,Risk Factors ,medicine ,Genetics ,PTEN ,Humans ,TP53 ,Neoplasm Metastasis ,skin and connective tissue diseases ,neoplasms ,Neoplasm Staging ,DNA methylation ,Gene Expression Profiling ,Methylation ,medicine.disease ,Prognosis ,Tumor Burden ,Receptors, Estrogen ,Oncology ,Mutation ,biology.protein ,Cancer research ,Early-Stage Breast Carcinoma ,CpG Islands ,Female ,Neoplasm Grading ,Tumor Suppressor Protein p53 ,Receptors, Progesterone ,Research Article ,Methylation index - Abstract
Background Aberrant DNA methylation of regulatory genes has frequently been found in human breast cancers and correlated to clinical outcome. In the present study we investigate stage specific changes in the DNA methylation patterns in order to identify valuable markers to understand how these changes affect breast cancer progression. Methods Quantitative DNA methylation analyses of 12 candidate genes ABCB1, BRCCA1, CDKN2A, ESR1, GSTP1, IGF2, MGMT, HMLH1, PPP2R2B, PTEN, RASSF1A and FOXC1 was performed by pyrosequencing a series of 238 breast cancer tissue samples from DCIS to invasive tumors stage I to IV. Results Significant differences in methylation levels between the DCIS and invasive stage II tumors were observed for six genes RASSF1A, CDKN2A, MGMT, ABCB1, GSTP1 and FOXC1. RASSF1A, ABCB1 and GSTP1 showed significantly higher methylation levels in late stage compared to the early stage breast carcinoma. Z-score analysis revealed significantly lower methylation levels in DCIS and stage I tumors compared with stage II, III and IV tumors. Methylation levels of PTEN, PPP2R2B, FOXC1, ABCB1 and BRCA1 were lower in tumors harboring TP53 mutations then in tumors with wild type TP53. Z-score analysis showed that TP53 mutated tumors had significantly lower overall methylation levels compared to tumors with wild type TP53. Methylation levels of RASSF1A, PPP2R2B, GSTP1 and FOXC1 were higher in ER positive vs. ER negative tumors and methylation levels of PTEN and CDKN2A were higher in HER2 positive vs. HER2 negative tumors. Z-score analysis also showed that HER2 positive tumors had significantly higher z-scores of methylation compared to the HER2 negative tumors. Univariate survival analysis identifies methylation status of PPP2R2B as significant predictor of overall survival and breast cancer specific survival. Conclusions In the present study we report that the level of aberrant DNA methylation is higher in late stage compared with early stage of invasive breast cancers and DCIS for genes mentioned above.
- Published
- 2013
14. Genome-wide DNA methylation profiles in progression to
- Author
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Jovana Klajic, Bjørn Naume, Hege Edvardsen, Anne Lise Børresen-Dale, Vessela N. Kristensen, Margit Riis, Åslaug Helland, Thomas Fleischer, Brock C. Christensen, Arnoldo Frigessi, Nizar Touleimat, Jörg Tost, Kevin C. Johnson, Vilde D. Haakensen, and Fredrik Wärnberg
- Subjects
Genetics ,DNA methylation ,Biology ,Genome - Published
- 2014
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