학술논문
Comprehensive molecular analysis of immortalization hallmarks in thyroid cancer reveals new prognostic markers.
Document Type
Academic Journal
Author
Montero-Conde C; Hereditary Endocrine Cancer Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.; Biomedical Research Networking Centre on Rare Diseases (CIBERER), Institute of Health Carlos III, Madrid, Spain.; Leandro-García LJ; Hereditary Endocrine Cancer Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.; Martínez-Montes ÁM; Hereditary Endocrine Cancer Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.; Martínez P; Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.; Moya FJ; Molecular Cytogenetics Unit, Human Cancer Genetics Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain.; Letón R; Hereditary Endocrine Cancer Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.; Gil E; Hereditary Endocrine Cancer Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.; Martínez-Puente N; Hereditary Endocrine Cancer Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.; Biomedical Research Networking Centre on Rare Diseases (CIBERER), Institute of Health Carlos III, Madrid, Spain.; Guadalix S; Department of Endocrinology, Hospital Universitario 12 de Octubre, Madrid, Spain.; Currás-Freixes M; Department of Endocrinology, Clínica Universidad de Navarra, Madrid, Spain.; Familial Cancer Clinical Unit, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.; García-Tobar L; Anatomical Pathology Section, Clínica Universidad de Navarra, Pamplona, Spain.; Zafon C; Department of Endocrinology, Hospital Universitari Vall d'Hebron, Barcelona, Spain.; Jordà M; Program for Predictive and Personalized Medicine of Cancer (PMPPC), Germans Trias i Pujol Research Institute (IGTP), Badalona, Spain.; Riesco-Eizaguirre G; Department of Endocrinology and Nutrition, Hospital Universitario de Móstoles, Madrid, Spain.; Endocrinology Molecular Group, Faculty of Medicine, Universidad Francisco de Vitoria, Madrid, Spain.; González-García P; Histopathology Unit, Biotechnology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain.; Monteagudo M; Hereditary Endocrine Cancer Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.; Torres-Pérez R; Hereditary Endocrine Cancer Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.; Bioinformatics for Genomics and Proteomics, National Centre for Biotechnology (CNB-CSIC), Madrid, Spain.; Mancikova V; Hereditary Endocrine Cancer Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.; Ruiz-Llorente S; Department of Biomedicine and Biotechnology, Universidad de Alcalá (UAH), Alcalá de Henares, Spain.; Pérez-Martínez M; Confocal Microscopy Unit, Biotechnology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain.; Pita G; CEGEN Unit, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.; Galofré JC; Department of Endocrinology, Clínica Universidad de Navarra, Pamplona, Spain.; Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain.; Gonzalez-Neira A; Biomedical Research Networking Centre on Rare Diseases (CIBERER), Institute of Health Carlos III, Madrid, Spain.; CEGEN Unit, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.; Cascón A; Hereditary Endocrine Cancer Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.; Biomedical Research Networking Centre on Rare Diseases (CIBERER), Institute of Health Carlos III, Madrid, Spain.; Rodríguez-Antona C; Hereditary Endocrine Cancer Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.; Biomedical Research Networking Centre on Rare Diseases (CIBERER), Institute of Health Carlos III, Madrid, Spain.; Megías D; Confocal Microscopy Unit, Biotechnology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain.; Blasco MA; Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.; Caleiras E; Histopathology Unit, Biotechnology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain.; Rodríguez-Perales S; Molecular Cytogenetics Unit, Human Cancer Genetics Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain.; Robledo M; Hereditary Endocrine Cancer Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.; Biomedical Research Networking Centre on Rare Diseases (CIBERER), Institute of Health Carlos III, Madrid, Spain.
Source
Publisher: Wiley Country of Publication: United States NLM ID: 101597971 Publication Model: Print Cited Medium: Internet ISSN: 2001-1326 (Electronic) Linking ISSN: 20011326 NLM ISO Abbreviation: Clin Transl Med Subsets: MEDLINE
Subject
Language
English
Abstract
Background: Comprehensive molecular studies on tumours are needed to delineate immortalization process steps and identify sensitive prognostic biomarkers in thyroid cancer.
Methods and Results: In this study, we extensively characterize telomere-related alterations in a series of 106 thyroid tumours with heterogeneous clinical outcomes. Using a custom-designed RNA-seq panel, we identified five telomerase holoenzyme-complex genes upregulated in clinically aggressive tumours compared to tumours from long-term disease-free patients, being TERT and TERC denoted as independent prognostic markers by multivariate regression model analysis. Characterization of alterations related to TERT re-expression revealed that promoter mutations, methylation and/or copy gains exclusively co-occurred in clinically aggressive tumours. Quantitative-FISH (fluorescence in situ hybridization) analysis of telomere lengths showed a significant shortening in these carcinomas, which matched with a high proliferative rate measured by Ki-67 immunohistochemistry. RNA-seq data analysis indicated that short-telomere tumours exhibit an increased transcriptional activity in the 5-Mb-subtelomeric regions, site of several telomerase-complex genes. Gene upregulation enrichment was significant for specific chromosome-ends such as the 5p, where TERT is located. Co-FISH analysis of 5p-end and TERT loci showed a more relaxed chromatin configuration in short telomere-length tumours compared to normal telomere-length tumours.
Conclusions: Overall, our findings support that telomere shortening leads to a 5p subtelomeric region reorganization, facilitating the transcription and accumulation of alterations at TERT-locus.
(© 2022 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)
Methods and Results: In this study, we extensively characterize telomere-related alterations in a series of 106 thyroid tumours with heterogeneous clinical outcomes. Using a custom-designed RNA-seq panel, we identified five telomerase holoenzyme-complex genes upregulated in clinically aggressive tumours compared to tumours from long-term disease-free patients, being TERT and TERC denoted as independent prognostic markers by multivariate regression model analysis. Characterization of alterations related to TERT re-expression revealed that promoter mutations, methylation and/or copy gains exclusively co-occurred in clinically aggressive tumours. Quantitative-FISH (fluorescence in situ hybridization) analysis of telomere lengths showed a significant shortening in these carcinomas, which matched with a high proliferative rate measured by Ki-67 immunohistochemistry. RNA-seq data analysis indicated that short-telomere tumours exhibit an increased transcriptional activity in the 5-Mb-subtelomeric regions, site of several telomerase-complex genes. Gene upregulation enrichment was significant for specific chromosome-ends such as the 5p, where TERT is located. Co-FISH analysis of 5p-end and TERT loci showed a more relaxed chromatin configuration in short telomere-length tumours compared to normal telomere-length tumours.
Conclusions: Overall, our findings support that telomere shortening leads to a 5p subtelomeric region reorganization, facilitating the transcription and accumulation of alterations at TERT-locus.
(© 2022 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)