Comprehensive molecular analysis of immortalization hallmarks in thyroid cancer reveals new prognostic markers
Por:
Montero-Conde, C, Leandro-Garcia, LJ, Martinez-Montes, AM, Martinez, P, Moya, FJ, Leton, R, Gil, E, Martinez-Puente, N, Guadalix, S, Curras-Freixes, M, Garcia-Tobar, L, Zafon, C, Jorda, M, Riesco-Eizaguirre, G, Gonzalez-Garcia, P, Monteagudo, M, Torres-Perez, R, Mancikova, V, Ruiz-Llorente, S, Perez-Martinez, M, Pita, G, Galofre, JC, Gonzalez-Neira, A, Cascon, A, Rodriguez-Antona, C, Megias, D, Blasco, MA, Caleiras, E, Rodriguez-Perales, S and Robledo, M
Publicada:
1 ago 2022
Resumen:
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.
Filiaciones:
Montero-Conde, C:
Spanish Natl Canc Res Ctr CNIO, Hereditary Endocrine Canc Grp, Human Canc Genet Program, C Melchor Fernandez Almagro 3, Madrid 28029, Spain
Inst Hlth Carlos III, Biomed Res Networking Ctr Rare Dis CIBERER, Madrid, Spain
Leandro-Garcia, LJ:
Spanish Natl Canc Res Ctr CNIO, Hereditary Endocrine Canc Grp, Human Canc Genet Program, C Melchor Fernandez Almagro 3, Madrid 28029, Spain
Martinez-Montes, AM:
Spanish Natl Canc Res Ctr CNIO, Hereditary Endocrine Canc Grp, Human Canc Genet Program, C Melchor Fernandez Almagro 3, Madrid 28029, Spain
Martinez, P:
Spanish Natl Canc Res Ctr CNIO, Telomeres & Telomerase Grp, Mol Oncol Program, Madrid, Spain
Moya, FJ:
Spanish Natl Canc Res Ctr CNIO, Mol Cytogenet Unit, Human Canc Genet Program, Madrid, Spain
Leton, R:
Spanish Natl Canc Res Ctr CNIO, Hereditary Endocrine Canc Grp, Human Canc Genet Program, C Melchor Fernandez Almagro 3, Madrid 28029, Spain
Gil, E:
Spanish Natl Canc Res Ctr CNIO, Hereditary Endocrine Canc Grp, Human Canc Genet Program, C Melchor Fernandez Almagro 3, Madrid 28029, Spain
Martinez-Puente, N:
Spanish Natl Canc Res Ctr CNIO, Hereditary Endocrine Canc Grp, Human Canc Genet Program, C Melchor Fernandez Almagro 3, Madrid 28029, Spain
Inst Hlth Carlos III, Biomed Res Networking Ctr Rare Dis CIBERER, Madrid, Spain
Guadalix, S:
Hosp Univ 12 Octubre, Dept Endocrinol, Madrid, Spain
Curras-Freixes, M:
Clin Univ Navarra, Dept Endocrinol, Madrid, Spain
Spanish Natl Canc Res Ctr CNIO, Familial Canc Clin Unit, Human Canc Genet Program, Madrid, Spain
Garcia-Tobar, L:
Clin Univ Navarra, Anat Pathol Sect, Pamplona, Spain
Zafon, C:
Hosp Univ Vall dHebron, Dept Endocrinol, Barcelona, Spain
:
Germans Trias & Pujol Res Inst IGTP, Program Predict & Personalized Med Canc PMPPC, Badalona, Spain
Riesco-Eizaguirre, G:
Hosp Univ Mostoles, Dept Endocrinol & Nutr, Madrid, Spain
Univ Francisco Vitoria, Endocrinol Mol Grp, Fac Med, Madrid, Spain
Gonzalez-Garcia, P:
Spanish Natl Canc Res Ctr CNIO, Histopathol Unit, Biotechnol Program, Madrid, Spain
Monteagudo, M:
Spanish Natl Canc Res Ctr CNIO, Hereditary Endocrine Canc Grp, Human Canc Genet Program, C Melchor Fernandez Almagro 3, Madrid 28029, Spain
Torres-Perez, R:
Spanish Natl Canc Res Ctr CNIO, Hereditary Endocrine Canc Grp, Human Canc Genet Program, C Melchor Fernandez Almagro 3, Madrid 28029, Spain
CSIC, Bioinformat Genom & Prote, Natl Ctr Biotechnol CNB, Madrid, Spain
Mancikova, V:
Spanish Natl Canc Res Ctr CNIO, Hereditary Endocrine Canc Grp, Human Canc Genet Program, C Melchor Fernandez Almagro 3, Madrid 28029, Spain
Ruiz-Llorente, S:
Univ Alcala UAH, Dept Biomed & Biotechnol, Alcala De Henares, Spain
Perez-Martinez, M:
Spanish Natl Canc Res Ctr CNIO, Confocal Microscopy Unit, Biotechnol Program, Madrid, Spain
Pita, G:
Spanish Natl Canc Res Ctr CNIO, CEGEN Unit, Human Canc Genet Program, Madrid, Spain
Galofre, JC:
Clin Univ Navarra, Dept Endocrinol, Pamplona, Spain
Inst Invest Sanitaria Navarra IdiSNA, Pamplona, Spain
Gonzalez-Neira, A:
Inst Hlth Carlos III, Biomed Res Networking Ctr Rare Dis CIBERER, Madrid, Spain
Spanish Natl Canc Res Ctr CNIO, CEGEN Unit, Human Canc Genet Program, Madrid, Spain
Cascon, A:
Spanish Natl Canc Res Ctr CNIO, Hereditary Endocrine Canc Grp, Human Canc Genet Program, C Melchor Fernandez Almagro 3, Madrid 28029, Spain
Inst Hlth Carlos III, Biomed Res Networking Ctr Rare Dis CIBERER, Madrid, Spain
Rodriguez-Antona, C:
Spanish Natl Canc Res Ctr CNIO, Hereditary Endocrine Canc Grp, Human Canc Genet Program, C Melchor Fernandez Almagro 3, Madrid 28029, Spain
Inst Hlth Carlos III, Biomed Res Networking Ctr Rare Dis CIBERER, Madrid, Spain
Megias, D:
Spanish Natl Canc Res Ctr CNIO, Confocal Microscopy Unit, Biotechnol Program, Madrid, Spain
Blasco, MA:
Spanish Natl Canc Res Ctr CNIO, Telomeres & Telomerase Grp, Mol Oncol Program, Madrid, Spain
Caleiras, E:
Spanish Natl Canc Res Ctr CNIO, Histopathol Unit, Biotechnol Program, Madrid, Spain
Rodriguez-Perales, S:
Spanish Natl Canc Res Ctr CNIO, Mol Cytogenet Unit, Human Canc Genet Program, Madrid, Spain
Robledo, M:
Spanish Natl Canc Res Ctr CNIO, Hereditary Endocrine Canc Grp, Human Canc Genet Program, C Melchor Fernandez Almagro 3, Madrid 28029, Spain
Inst Hlth Carlos III, Biomed Res Networking Ctr Rare Dis CIBERER, Madrid, Spain
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