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1. Supplementary data for the biological age linked to oxidative stress modifies breast cancer aggressiveness

Author

del Mar Sáez-Freire, María, Blanco-Gómez, Adrián, Castillo-Lluva, Sonia, Gómez-Vecino, Aurora, Galvis-Jiménez, Julie Milena, Martín-Seisdedos, Carmen, Isidoro-García, María, Hontecillas-Prieto, Lourdes, García-Cenador, María Begoña, García-Criado, Francisco Javier, Patino-Alonso, María Carmen, Galindo-Villardón, Purificación, Mao, Jian-Hua, Prieto, Carlos, Castellanos-Martín, Andrés, Kaderali, Lars, and Pérez-Losada, Jesús

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Aging, Cancer, Breast Cancer, Good Health and Well Being
Abstract

The data presented in this article are related to the research paper entitled "The biological age linked to oxidative stress modifies breast cancer aggressiveness" (M.M. Sáez-Freire, A. Blanco-Gómez, S. Castillo-Lluva, A. Gómez-Vecino, J.M. Galvis-Jiménez, C. Martín-Seisdedos, M. Isidoro-García, L. Hontecillas-Prieto, M.B. García-Cenador, F.J. García-Criado, M.C. Patino-Alonso, P. Galindo-Villardón, J.H. Mao, C. Prieto, A. Castellanos-Martín, L. Kaderali, J. Pérez-Losada). The data shown were obtained from a population of transgenic mice, MMTV-Erbb2/Neu, with different susceptibility to breast cancer and a mixed genetic background generated by backcrossing. It was observed that the aggressiveness of breast cancer negatively correlates with age, being lower in chronologically old mice, similar to what occurs in humans. Given that oxidative stress is associated with tumour susceptibility and the degree of aging, the association between the aggressiveness of breast cancer and multiple intermediate phenotypes directly or indirectly related to oxidative stress was studied. Using a mathematical model, we defined biological age and the degree of aging as the difference between biological and chronological ages. As a result, we observed that biologically old mice predominated among those that developed the disease early on, that is, those that were chronologically young. We then identified the specific and common genetic components of Quantitative Trait loci or QTL associated with different evolution of breast cancer, the intermediate phenotypes related to oxidative stress studied, the biological age and the degree of aging. Lastly, we showed that the expression pattern in the livers of biologically old mice were enriched in signalling pathways related to inflammation and response to infections; whereas the biologically young mice exhibited enriched pathways related to mitochondrial activity. For the explanation and discussion of these data refer to the research article cited above.

Published
2018

2. Supplementary data for the biological age linked to oxidative stress modifies breast cancer aggressiveness.

Author

Sáez-Freire, María Del Mar, Blanco-Gómez, Adrián, Castillo-Lluva, Sonia, Gómez-Vecino, Aurora, Galvis-Jiménez, Julie Milena, Martín-Seisdedos, Carmen, Isidoro-García, María, Hontecillas-Prieto, Lourdes, García-Cenador, María Begoña, García-Criado, Francisco Javier, Patino-Alonso, María Carmen, Galindo-Villardón, Purificación, Mao, Jian-Hua, Prieto, Carlos, Castellanos-Martín, Andrés, Kaderali, Lars, and Pérez-Losada, Jesús

Abstract

The data presented in this article are related to the research paper entitled "The biological age linked to oxidative stress modifies breast cancer aggressiveness" (M.M. Sáez-Freire, A. Blanco-Gómez, S. Castillo-Lluva, A. Gómez-Vecino, J.M. Galvis-Jiménez, C. Martín-Seisdedos, M. Isidoro-García, L. Hontecillas-Prieto, M.B. García-Cenador, F.J. García-Criado, M.C. Patino-Alonso, P. Galindo-Villardón, J.H. Mao, C. Prieto, A. Castellanos-Martín, L. Kaderali, J. Pérez-Losada). The data shown were obtained from a population of transgenic mice, MMTV-Erbb2/Neu, with different susceptibility to breast cancer and a mixed genetic background generated by backcrossing. It was observed that the aggressiveness of breast cancer negatively correlates with age, being lower in chronologically old mice, similar to what occurs in humans. Given that oxidative stress is associated with tumour susceptibility and the degree of aging, the association between the aggressiveness of breast cancer and multiple intermediate phenotypes directly or indirectly related to oxidative stress was studied. Using a mathematical model, we defined biological age and the degree of aging as the difference between biological and chronological ages. As a result, we observed that biologically old mice predominated among those that developed the disease early on, that is, those that were chronologically young. We then identified the specific and common genetic components of Quantitative Trait loci or QTL associated with different evolution of breast cancer, the intermediate phenotypes related to oxidative stress studied, the biological age and the degree of aging. Lastly, we showed that the expression pattern in the livers of biologically old mice were enriched in signalling pathways related to inflammation and response to infections; whereas the biologically young mice exhibited enriched pathways related to mitochondrial activity. For the explanation and discussion of these data refer to the research article cited above.

Published
2018

3. The biological age linked to oxidative stress modifies breast cancer aggressiveness

Author

Sáez-Freire, María Del Mar, Blanco-Gómez, Adrián, Castillo-Lluva, Sonia, Gómez-Vecino, Aurora, Galvis-Jiménez, Julie Milena, Martín-Seisdedos, Carmen, Isidoro-García, María, Hontecillas-Prieto, Lourdes, García-Cenador, María Begoña, García-Criado, Francisco Javier, Patino-Alonso, María Carmen, Galindo-Villardón, Purificación, Mao, Jian-Hua, Prieto, Carlos, Castellanos-Martín, Andrés, Kaderali, Lars, and Pérez-Losada, Jesús

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Digestive Diseases, Breast Cancer, Liver Disease, Genetics, Cancer, Aging, Biotechnology, Aetiology, 2.1 Biological and endogenous factors, Animals, Breast Neoplasms, Female, Genes, erbB-2, Glutathione, Inflammation, Liver, Mice, Mice, Inbred C57BL, Mice, Transgenic, Models, Theoretical, Oxidative Stress, Proto-Oncogene Proteins c-akt, Quantitative Trait Loci, Receptor, ErbB-2, Transcriptome, Breast cancer, Biological age, Mouse genetics, Oxidative stress, Subphenotypes, Receptor, erbB-2, Medicinal and Biomolecular Chemistry, Biochemistry and Cell Biology, Medical Biochemistry and Metabolomics, Biochemistry & Molecular Biology, Biochemistry and cell biology, Medical biochemistry and metabolomics
Abstract

The incidence of breast cancer increases with age until menopause, and breast cancer is more aggressive in younger women. The existence of epidemiological links between breast cancer and aging indicates that both processes share some common mechanisms of development. Oxidative stress is associated with both cancer susceptibility and aging. Here we observed that ERBB2-positive breast cancer, which developed in genetically heterogeneous ERBB2-positive transgenic mice generated by a backcross, is more aggressive in chronologically younger than in older mice (differentiated by the median survival of the cohort that was 79 weeks), similar to what occurs in humans. In this cohort, we estimated the oxidative biological age using a mathematical model that integrated several subphenotypes directly or indirectly related to oxidative stress. The model selected the serum levels of HDL-cholesterol and magnesium and total AKT1 and glutathione concentrations in the liver. The grade of aging was calculated as the difference between the predicted biological age and the chronological age. This comparison permitted the identification of biologically younger and older mice compared with their chronological age. Interestingly, biologically older mice developed more aggressive breast cancer than the biologically younger mice. Genomic regions on chromosomes 2 and 15 linked to the grade of oxidative aging were identified. The levels of expression of Zbp1 located on chromosome 2, a gene related to necroptosis and inflammation, positively correlated with the grade of aging and tumour aggressiveness. Moreover, the pattern of gene expression of genes linked to the inflammation and the response to infection pathways was enriched in the livers of biologically old mice. This study shows part of the complex interactions between breast cancer and aging.

Published
2018

4. Intermediate Molecular Phenotypes to Identify Genetic Markers of Anthracycline-Induced Cardiotoxicity Risk

Author

Gómez-Vecino, Aurora, primary, Corchado-Cobos, Roberto, additional, Blanco-Gómez, Adrián, additional, García-Sancha, Natalia, additional, Castillo-Lluva, Sonia, additional, Martín-García, Ana, additional, Mendiburu-Eliçabe, Marina, additional, Prieto, Carlos, additional, Ruiz-Pinto, Sara, additional, Pita, Guillermo, additional, Velasco-Ruiz, Alejandro, additional, Patino-Alonso, Carmen, additional, Galindo-Villardón, Purificación, additional, Vera-Pedrosa, María Linarejos, additional, Jalife, José, additional, Mao, Jian-Hua, additional, Macías de Plasencia, Guillermo, additional, Castellanos-Martín, Andrés, additional, Sáez-Freire, María del Mar, additional, Fraile-Martín, Susana, additional, Rodrigues-Teixeira, Telmo, additional, García-Macías, Carmen, additional, Galvis-Jiménez, Julie Milena, additional, García-Sánchez, Asunción, additional, Isidoro-García, María, additional, Fuentes, Manuel, additional, García-Cenador, María Begoña, additional, García-Criado, Francisco Javier, additional, García-Hernández, Juan Luis, additional, Hernández-García, María Ángeles, additional, Cruz-Hernández, Juan Jesús, additional, Rodríguez-Sánchez, César Augusto, additional, García-Sancho, Alejandro Martín, additional, Pérez-López, Estefanía, additional, Pérez-Martínez, Antonio, additional, Gutiérrez-Larraya, Federico, additional, Cartón, Antonio J., additional, García-Sáenz, José Ángel, additional, Patiño-García, Ana, additional, Martín, Miguel, additional, Alonso-Gordoa, Teresa, additional, Vulsteke, Christof, additional, Croes, Lieselot, additional, Hatse, Sigrid, additional, Van Brussel, Thomas, additional, Lambrechts, Diether, additional, Wildiers, Hans, additional, Hang, Chang, additional, Holgado-Madruga, Marina, additional, González-Neira, Anna, additional, Sánchez, Pedro L., additional, and Pérez Losada, Jesús, additional

Published
2023
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5. Intermediate Molecular Phenotypes to Identify Genetic Markers of Anthracycline-Induced Cardiotoxicity Risk

Author

Gómez Vecino, Aurora, Corchado Cobos, Roberto, Blanco Gómez, Adrián, García Sancha, Natalia, Martín García, Ana, Mendiburu-Eliçabe Garganta, Marina, Prieto, Carlos, Ruiz Pinto, Sara, Pita, Guillermo, Velasco Ruiz, Alejandro, Patino Alonso, Carmen, Galindo Villardón, Purificación, Linarejos Vera Pedrosa, María, Jalife, José, Mao, Jian-Hua, Macías de Plasencia, Guillermo, Castellanos Martín, Andrés, Sáez Freire, María del Mar, Fraile Martín, Susana, Rodrigues Teixeira, Telmo, García Macías, Carmen, Galvis Jiménez, Julie Milena, Castillo Lluva, Sonia, García Sánchez, Asunción, Isidoro García, María, Fuentes, Manuel, García-Cenador, María Begoña, García-Criado, Francisco Javier, García-Hernández, Juan Luis, Hernández-García, María Ángeles, Cruz-Hernández, Juan Jesús, Rodríguez-Sánchez, César Augusto, Martín García-Sancho, Alejandro, Pérez-López, Estefanía, Pérez-Martínez, Antonio, Gutiérrez-Larraya, Federico, Cartón, Antonio J., García-Sáenz, José Ángel, Patiño-García, Ana, Martín, Miguel, Alonso-Gordoa, Teresa, Vulsteke, Christof, Croes, Lieselot, Hatse, Sigrid, Van Brussel, Thomas, Lambrechts, Diether, Wildiers, Hans, Hang, Chang, Holgado-Madruga, Marina, González-Neira, Anna, Sánchez, Pedro L., Pérez Losada, Jesús, Gómez Vecino, Aurora, Corchado Cobos, Roberto, Blanco Gómez, Adrián, García Sancha, Natalia, Martín García, Ana, Mendiburu-Eliçabe Garganta, Marina, Prieto, Carlos, Ruiz Pinto, Sara, Pita, Guillermo, Velasco Ruiz, Alejandro, Patino Alonso, Carmen, Galindo Villardón, Purificación, Linarejos Vera Pedrosa, María, Jalife, José, Mao, Jian-Hua, Macías de Plasencia, Guillermo, Castellanos Martín, Andrés, Sáez Freire, María del Mar, Fraile Martín, Susana, Rodrigues Teixeira, Telmo, García Macías, Carmen, Galvis Jiménez, Julie Milena, Castillo Lluva, Sonia, García Sánchez, Asunción, Isidoro García, María, Fuentes, Manuel, García-Cenador, María Begoña, García-Criado, Francisco Javier, García-Hernández, Juan Luis, Hernández-García, María Ángeles, Cruz-Hernández, Juan Jesús, Rodríguez-Sánchez, César Augusto, Martín García-Sancho, Alejandro, Pérez-López, Estefanía, Pérez-Martínez, Antonio, Gutiérrez-Larraya, Federico, Cartón, Antonio J., García-Sáenz, José Ángel, Patiño-García, Ana, Martín, Miguel, Alonso-Gordoa, Teresa, Vulsteke, Christof, Croes, Lieselot, Hatse, Sigrid, Van Brussel, Thomas, Lambrechts, Diether, Wildiers, Hans, Hang, Chang, Holgado-Madruga, Marina, González-Neira, Anna, Sánchez, Pedro L., and Pérez Losada, Jesús

Abstract

Cardiotoxicity due to anthracyclines (CDA) affects cancer patients, but we cannot predict who may suffer from this complication. CDA is a complex trait with a polygenic component that is mainly unidentified. We propose that levels of intermediate molecular phenotypes (IMPs) in the myocardium associated with histopathological damage could explain CDA susceptibility, so variants of genes encoding these IMPs could identify patients susceptible to this complication. Thus, a genetically heterogeneous cohort of mice (n = 165) generated by backcrossing were treated with doxorubicin and docetaxel. We quantified heart fibrosis using an Ariol slide scanner and intramyocardial levels of IMPs using multiplex bead arrays and QPCR. We identified quantitative trait loci linked to IMPs (ipQTLs) and cdaQTLs via linkage analysis. In three cancer patient cohorts, CDA was quantified using echocardiography or Cardiac Magnetic Resonance. CDA behaves as a complex trait in the mouse cohort. IMP levels in the myocardium were associated with CDA. ipQTLs integrated into genetic models with cdaQTLs account for more CDA phenotypic variation than that explained by cda-QTLs alone. Allelic forms of genes encoding IMPs associated with CDA in mice, including AKT1, MAPK14, MAPK8, STAT3, CAS3, and TP53, are genetic determinants of CDA in patients. Two genetic risk scores for pediatric patients (n = 71) and women with breast cancer (n = 420) were generated using machine-learning Least Absolute Shrinkage and Selection Operator (LASSO) regression. Thus, IMPs associated with heart damage identify genetic markers of CDA risk, thereby allowing more personalized patient management., Ministerio de Ciencia, Innovación y Universidades (España), European Comission, Junta de Castilla y León, Instituto de Salud Carlos III, Ministerio de Economía, Comercio y Empresa (España), Federación Española de Enfermedades Raras, Departamento de Defensa (Estados Unidos), National Institutes of Health (Estados Unidos), Universidad de California (Estados Unidos), Instituto Nacional del Cáncer (Estados Unidos), Fundación "la Caixa", Agencia Estatal de Investigación, Depto. de Estadística e Investigación Operativa, Fac. de Farmacia, TRUE, pub

Published
2023

6. Intermediate Molecular Phenotypes to Identify Genetic Markers of Anthracycline-Induced Cardiotoxicity Risk

Author

Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), European Commission, Junta de Castilla y León, Instituto de Salud Carlos III, Department of Defense (US), National Institutes of Health (US), National Cancer Institute (US), Lawrence Berkeley National Laboratory, Fundación la Caixa, Centro Nacional de Investigaciones Cardiovasculares (España), Gómez-Vecino, Aurora, Corchado Cobos, Roberto, Blanco-Gómez, Adrián, García-Sancha, Natalia, Castillo-Lluva, Sonia, Martin-Garcia, Ana, Mendiburu-Eliçabe, Marina, Prieto, Carlos, Ruiz-Pinto, Sara, Pita, Guillermo, Velasco-Ruiz, Alejandro, Patino-Alonso, María Carmen, Galindo-Villardón, Purificación, Linarejos Vera-Pedrosa, María, Jalife, José, Mao, Jian-Hua, Macías de Plasencia, Guillermo, Castellanos-Martín, Andrés, Sáez-Freire, María Del Mar, Fraile, Susana, Rodrigues Teixeira, Telmo, García-Macías, Carmen, Galvis-Jiménez, Julie Milena, García Sánchez, Asunción, Isidoro-García, María, Fuentes, Manuel, García-Cenador, Begoña, García-Criado, Francisco Javier, García, Juan L., Hernández-García, María Ángeles, Cruz, Juan Jesús, Rodríguez-Sánchez, César Augusto, García-Sancho, Alejandro Martín, Pérez-López, Estefanía, Pérez-Martínez, Antonio, Gutiérrez-Larraya, Federico, Cartón, Antonio J, García-Sáenz, José Ángel, Patiño-García, Ana, Martín, Miguel, Alonso Gordoa, Teresa, Vulsteke, Christof, Croes, Lieselot, Hatse, Sigrid, Van Brussel, Thomas, Lambrechts, Diether, Wildiers, Hans, Chang, Hang, Holgado-Madruga, M., González-Neira, Anna, Sánchez, Pedro L, Pérez-Losada, J., Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), European Commission, Junta de Castilla y León, Instituto de Salud Carlos III, Department of Defense (US), National Institutes of Health (US), National Cancer Institute (US), Lawrence Berkeley National Laboratory, Fundación la Caixa, Centro Nacional de Investigaciones Cardiovasculares (España), Gómez-Vecino, Aurora, Corchado Cobos, Roberto, Blanco-Gómez, Adrián, García-Sancha, Natalia, Castillo-Lluva, Sonia, Martin-Garcia, Ana, Mendiburu-Eliçabe, Marina, Prieto, Carlos, Ruiz-Pinto, Sara, Pita, Guillermo, Velasco-Ruiz, Alejandro, Patino-Alonso, María Carmen, Galindo-Villardón, Purificación, Linarejos Vera-Pedrosa, María, Jalife, José, Mao, Jian-Hua, Macías de Plasencia, Guillermo, Castellanos-Martín, Andrés, Sáez-Freire, María Del Mar, Fraile, Susana, Rodrigues Teixeira, Telmo, García-Macías, Carmen, Galvis-Jiménez, Julie Milena, García Sánchez, Asunción, Isidoro-García, María, Fuentes, Manuel, García-Cenador, Begoña, García-Criado, Francisco Javier, García, Juan L., Hernández-García, María Ángeles, Cruz, Juan Jesús, Rodríguez-Sánchez, César Augusto, García-Sancho, Alejandro Martín, Pérez-López, Estefanía, Pérez-Martínez, Antonio, Gutiérrez-Larraya, Federico, Cartón, Antonio J, García-Sáenz, José Ángel, Patiño-García, Ana, Martín, Miguel, Alonso Gordoa, Teresa, Vulsteke, Christof, Croes, Lieselot, Hatse, Sigrid, Van Brussel, Thomas, Lambrechts, Diether, Wildiers, Hans, Chang, Hang, Holgado-Madruga, M., González-Neira, Anna, Sánchez, Pedro L, and Pérez-Losada, J.

Abstract

Cardiotoxicity due to anthracyclines (CDA) affects cancer patients, but we cannot predict who may suffer from this complication. CDA is a complex trait with a polygenic component that is mainly unidentified. We propose that levels of intermediate molecular phenotypes (IMPs) in the myocardium associated with histopathological damage could explain CDA susceptibility, so variants of genes encoding these IMPs could identify patients susceptible to this complication. Thus, a genetically heterogeneous cohort of mice (n = 165) generated by backcrossing were treated with doxorubicin and docetaxel. We quantified heart fibrosis using an Ariol slide scanner and intramyocardial levels of IMPs using multiplex bead arrays and QPCR. We identified quantitative trait loci linked to IMPs (ipQTLs) and cdaQTLs via linkage analysis. In three cancer patient cohorts, CDA was quantified using echocardiography or Cardiac Magnetic Resonance. CDA behaves as a complex trait in the mouse cohort. IMP levels in the myocardium were associated with CDA. ipQTLs integrated into genetic models with cdaQTLs account for more CDA phenotypic variation than that explained by cda-QTLs alone. Allelic forms of genes encoding IMPs associated with CDA in mice, including AKT1, MAPK14, MAPK8, STAT3, CAS3, and TP53, are genetic determinants of CDA in patients. Two genetic risk scores for pediatric patients (n = 71) and women with breast cancer (n = 420) were generated using machine-learning Least Absolute Shrinkage and Selection Operator (LASSO) regression. Thus, IMPs associated with heart damage identify genetic markers of CDA risk, thereby allowing more personalized patient management.

Published
2023

7. Datasets related to a study aimed to identify genetic markers of CDA by subphenotypes associated with cardiotoxicity

Author

European Commission, Ministerio de Ciencia, Innovación y Universidades (España), Ministerio de Economía y Competitividad (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, Junta de Castilla y León, Fundación la Caixa, Centro Nacional de Investigaciones Cardiovasculares (España), Pérez-Losada, J. [0000-0003-2400-624X], Macías de Plasencia, Guillermo, Fraile, Susana, Rodrigues Teixeira, Telmo, Hernández-García, María Ángeles, Holgado-Madruga, M., González-Neira, Ana, Sánchez, Pedro L., Pérez-Losada, J., Gómez-Vecino, Aurora, Corchado Cobos, Roberto, Blanco-Gómez, Adrián, Castillo, Sonia, García-Sancha, Natalia, Martin-Garcia, Ana, Prieto, Carlos, Ruiz-Pinto, Sara, Pita, Guillermo, Velasco-Ruiz, Alejandro, Patino-Alonso, María Carmen, Galindo-Villardón, Purificación, Linarejos Vera-Pedrosa, María, Jalife, José, Castellanos-Martín, Andrés, Sáez-Freire, María del Mar, Mendiburu-Eliçabe, Marina, García-Macías, Carmen, Galvis-Jiménez, Julie Milena, García-Sánchez, Asunción, Isidoro-García, María, Fuentes, Manuel, García-Cenador, Begoña, García-Criado, Francisco Javier, García, Juan L., Cruz, Juan Jesús, Rodríguez-Sánchez, César Augusto, Martín-Ruiz, Alejandro, Pérez-López, Estefanía, Pérez-Martínez, Antonio, Gutiérrez-Larraya, Federico, Cartón, Antonio J., García-Saenz, José Ángel, Patiño-García, Ana, Martin, Miguel, Alonso Gordoa, Teresa, Vulsteke, Christof, Croes, Lieselot, Hatse, Sigrid, Van Brussel, Thomas, Lambrechts, Diether, Wildiers, Hans, Martín, Miguel A., European Commission, Ministerio de Ciencia, Innovación y Universidades (España), Ministerio de Economía y Competitividad (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, Junta de Castilla y León, Fundación la Caixa, Centro Nacional de Investigaciones Cardiovasculares (España), Pérez-Losada, J. [0000-0003-2400-624X], Macías de Plasencia, Guillermo, Fraile, Susana, Rodrigues Teixeira, Telmo, Hernández-García, María Ángeles, Holgado-Madruga, M., González-Neira, Ana, Sánchez, Pedro L., Pérez-Losada, J., Gómez-Vecino, Aurora, Corchado Cobos, Roberto, Blanco-Gómez, Adrián, Castillo, Sonia, García-Sancha, Natalia, Martin-Garcia, Ana, Prieto, Carlos, Ruiz-Pinto, Sara, Pita, Guillermo, Velasco-Ruiz, Alejandro, Patino-Alonso, María Carmen, Galindo-Villardón, Purificación, Linarejos Vera-Pedrosa, María, Jalife, José, Castellanos-Martín, Andrés, Sáez-Freire, María del Mar, Mendiburu-Eliçabe, Marina, García-Macías, Carmen, Galvis-Jiménez, Julie Milena, García-Sánchez, Asunción, Isidoro-García, María, Fuentes, Manuel, García-Cenador, Begoña, García-Criado, Francisco Javier, García, Juan L., Cruz, Juan Jesús, Rodríguez-Sánchez, César Augusto, Martín-Ruiz, Alejandro, Pérez-López, Estefanía, Pérez-Martínez, Antonio, Gutiérrez-Larraya, Federico, Cartón, Antonio J., García-Saenz, José Ángel, Patiño-García, Ana, Martin, Miguel, Alonso Gordoa, Teresa, Vulsteke, Christof, Croes, Lieselot, Hatse, Sigrid, Van Brussel, Thomas, Lambrechts, Diether, Wildiers, Hans, and Martín, Miguel A.

Abstract

Here we present a series of supplemental datasets that complement our study entitled "A Systems Genetics approach to identify genetic markers of cardiotoxicity due to anthracyclines in cancer patients." The datasets presented here were used to generate the main and supplementary figures and tables of the indicated study. The study consists of the identification of genetic markers of cardiotoxicity due to anthracyclines (CDA). CDA is a complex genesis disease or complex trait, and because of this, there is a component of missing heritability. Therefore, it is not possible to identify genetic markers associated with CDA risk. Here, we propose that molecular subphenotypes associated with the CDA may be a strategy for identifying some of this missing heritability and risk markers associated with it. A similar strategy could be applied to identify markers of other diseases of complex genesis. This study is done using a genetically heterogeneous cohort of mice that developed breast cancer and was treated with doxorubicin or a combined treatment of doxorubicin and docetaxel. The mouse cohort was generated by backcrossing, so each mouse is genetically unique. Post-chemotherapy heart damage was assessed by quantifying fibrosis's cardiac area and the thickness of myocardial fibers. The genetic regions associated with CDA were assessed by massive genotyping and genetic linkage analysis. Several molecular subphenotypes were quantified in the myocardium, and their association with the CDA was evaluated. Subsequently, we identified which of them were most statistically associated with CDA in multivariate models. Moreover, which complex trait loci (QTLs) associated with molecular subphenotypes best explained CDA. This strategy served to identify in the cohort of mice genes whose allelic forms could be candidates for the risk of CDA. Allelic variants of these genes were evaluated in four cohorts of cancer patients treated with anthracyclines and whose CDA was evaluated by echocardi

Published
2021

8. Supplementary data for the biological age linked to oxidative stress modifies breast cancer aggressiveness

Author

Ministerio de Ciencia e Innovación (España), National Cancer Institute (US), Fundación Sandra Ibarra - Solidaridad Frente al Cáncer, Department of Energy (US), Instituto de Salud Carlos III, European Commission, National Institutes of Health (US), Sáez-Freire, María del Mar, Blanco-Gómez, Adrián, Castillo, Sonia, Gómez-Vecino, Aurora, Galvis-Jiménez, Julie Milena, Martín-Seisdedos, Carmen, Isidoro-García, María, Hontecillas-Prieto, Lourdes, García-Cenador, Begoña, García-Criado, Francisco Javier, Patino-Alonso, María Carmen, Galindo-Villardón, Purificación, Mao, Jian-Hua, Prieto, Carlos, Castellanos-Martín, Andrés, Kaderali, Lars, Pérez-Losada, J., Ministerio de Ciencia e Innovación (España), National Cancer Institute (US), Fundación Sandra Ibarra - Solidaridad Frente al Cáncer, Department of Energy (US), Instituto de Salud Carlos III, European Commission, National Institutes of Health (US), Sáez-Freire, María del Mar, Blanco-Gómez, Adrián, Castillo, Sonia, Gómez-Vecino, Aurora, Galvis-Jiménez, Julie Milena, Martín-Seisdedos, Carmen, Isidoro-García, María, Hontecillas-Prieto, Lourdes, García-Cenador, Begoña, García-Criado, Francisco Javier, Patino-Alonso, María Carmen, Galindo-Villardón, Purificación, Mao, Jian-Hua, Prieto, Carlos, Castellanos-Martín, Andrés, Kaderali, Lars, and Pérez-Losada, J.

Abstract

The data presented in this article are related to the research paper entitled “The biological age linked to oxidative stress modifies breast cancer aggressiveness” (M.M. Sáez-Freire, A. Blanco-Gómez, S. Castillo-Lluva, A. Gómez-Vecino, J.M. Galvis-Jiménez, C. Martín-Seisdedos, M. Isidoro-García, L. Hontecillas-Prieto, M.B. García-Cenador, F.J. García-Criado, M.C. Patino-Alonso, P. Galindo-Villardón, J.H. Mao, C. Prieto, A. Castellanos-Martín, L. Kaderali, J. Pérez-Losada). The data shown were obtained from a population of transgenic mice, MMTV-Erbb2/Neu, with different susceptibility to breast cancer and a mixed genetic background generated by backcrossing. It was observed that the aggressiveness of breast cancer negatively correlates with age, being lower in chronologically old mice, similar to what occurs in humans. Given that oxidative stress is associated with tumour susceptibility and the degree of aging, the association between the aggressiveness of breast cancer and multiple intermediate phenotypes directly or indirectly related to oxidative stress was studied. Using a mathematical model, we defined biological age and the degree of aging as the difference between biological and chronological ages. As a result, we observed that biologically old mice predominated among those that developed the disease early on, that is, those that were chronologically young. We then identified the specific and common genetic components of Quantitative Trait loci or QTL associated with different evolution of breast cancer, the intermediate phenotypes related to oxidative stress studied, the biological age and the degree of aging. Lastly, we showed that the expression pattern in the livers of biologically old mice were enriched in signalling pathways related to inflammation and response to infections; whereas the biologically young mice exhibited enriched pathways related to mitochondrial activity. For the explanation and discussion of these data refer to the research article cit

Published
2018

9. The biological age linked to oxidative stress modifies breast cancer aggressiveness

Author

Ministerio de Ciencia e Innovación (España), Instituto de Salud Carlos III, Ministerio de Economía y Competitividad (España), European Commission, Fundación Sandra Ibarra - Solidaridad Frente al Cáncer, National Institutes of Health (US), National Cancer Institute (US), Department of Energy (US), Sáez-Freire, María del Mar, Blanco-Gómez, Adrián, Castillo, Sonia, Gómez-Vecino, Aurora, Galvis-Jiménez, Julie Milena, Martín-Seisdedos, Carmen, Isidoro-García, María, Hontecillas-Prieto, Lourdes, García-Cenador, Begoña, García-Criado, Francisco Javier, Patino-Alonso, María Carmen, Galindo-Villardón, Purificación, Mao, Jian-Hua, Prieto, Carlos, Castellanos-Martín, Andrés, Kaderali, Lars, Pérez-Losada, J., Ministerio de Ciencia e Innovación (España), Instituto de Salud Carlos III, Ministerio de Economía y Competitividad (España), European Commission, Fundación Sandra Ibarra - Solidaridad Frente al Cáncer, National Institutes of Health (US), National Cancer Institute (US), Department of Energy (US), Sáez-Freire, María del Mar, Blanco-Gómez, Adrián, Castillo, Sonia, Gómez-Vecino, Aurora, Galvis-Jiménez, Julie Milena, Martín-Seisdedos, Carmen, Isidoro-García, María, Hontecillas-Prieto, Lourdes, García-Cenador, Begoña, García-Criado, Francisco Javier, Patino-Alonso, María Carmen, Galindo-Villardón, Purificación, Mao, Jian-Hua, Prieto, Carlos, Castellanos-Martín, Andrés, Kaderali, Lars, and Pérez-Losada, J.

Abstract

The incidence of breast cancer increases with age until menopause, and breast cancer is more aggressive in younger women. The existence of epidemiological links between breast cancer and aging indicates that both processes share some common mechanisms of development. Oxidative stress is associated with both cancer susceptibility and aging. Here we observed that ERBB2-positive breast cancer, which developed in genetically heterogeneous ERBB2-positive transgenic mice generated by a backcross, is more aggressive in chronologically younger than in older mice (differentiated by the median survival of the cohort that was 79 weeks), similar to what occurs in humans. In this cohort, we estimated the oxidative biological age using a mathematical model that integrated several subphenotypes directly or indirectly related to oxidative stress. The model selected the serum levels of HDL-cholesterol and magnesium and total AKT1 and glutathione concentrations in the liver. The grade of aging was calculated as the difference between the predicted biological age and the chronological age. This comparison permitted the identification of biologically younger and older mice compared with their chronological age. Interestingly, biologically older mice developed more aggressive breast cancer than the biologically younger mice. Genomic regions on chromosomes 2 and 15 linked to the grade of oxidative aging were identified. The levels of expression of Zbp1 located on chromosome 2, a gene related to necroptosis and inflammation, positively correlated with the grade of aging and tumour aggressiveness. Moreover, the pattern of gene expression of genes linked to the inflammation and the response to infection pathways was enriched in the livers of biologically old mice. This study shows part of the complex interactions between breast cancer and aging.

Published
2018

10. Supplementary data for the biological age linked to oxidative stress modifies breast cancer aggressiveness

Author

Sáez-Freire, María del Mar, primary, Blanco-Gómez, Adrián, additional, Castillo-Lluva, Sonia, additional, Gómez-Vecino, Aurora, additional, Galvis-Jiménez, Julie Milena, additional, Martín-Seisdedos, Carmen, additional, Isidoro-García, María, additional, Hontecillas-Prieto, Lourdes, additional, García-Cenador, María Begoña, additional, García-Criado, Francisco Javier, additional, Patino-Alonso, María Carmen, additional, Galindo-Villardón, Purificación, additional, Mao, Jian-Hua, additional, Prieto, Carlos, additional, Castellanos-Martín, Andrés, additional, Kaderali, Lars, additional, and Pérez-Losada, Jesús, additional

Published
2018
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11. The biological age linked to oxidative stress modifies breast cancer aggressiveness

Author

Sáez-Freire, María del Mar, primary, Blanco-Gómez, Adrián, additional, Castillo-Lluva, Sonia, additional, Gómez-Vecino, Aurora, additional, Galvis-Jiménez, Julie Milena, additional, Martín-Seisdedos, Carmen, additional, Isidoro-García, María, additional, Hontecillas-Prieto, Lourdes, additional, García-Cenador, María Begoña, additional, García-Criado, Francisco Javier, additional, Patino-Alonso, María Carmen, additional, Galindo-Villardón, Purificación, additional, Mao, Jian-Hua, additional, Prieto, Carlos, additional, Castellanos-Martín, Andrés, additional, Kaderali, Lars, additional, and Pérez-Losada, Jesús, additional

Published
2018
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12. Analysis of genetic and phenotypic interactions between DNA damage / genotoxicity pathways in heart tissue and heart damage caused by anthracyclines and taxanes

Author

Corchado Cobos, Roberto, Gómez-Vecino, Aurora, García-Macías, Carmen, Rodrigues Teixeira, Telmo, Isidoro-García, María, García Sánchez, Asunción, Galvis-Jiménez, Julie Milena, Ramos, Isabel, Blanco-Gómez, Adrián, Sánchez-Fernández, Pedro Luis, and Pérez-Losada, J.

Abstract

Resumen del póster presentado al XXXIX Congreso de la Sociedad Española de Bioquímica y Biología Molecular, celebrado en Salamanca del 5 al 8 de septiembre de 2016., [Introduction]: Anthracyclines are among the most widely used chemotherapeutic agents in the treatment of a variety of tumors. The identification of genetic and molecular factors responsible for the increased risk of CDA (cardiotoxicity due to anthracyclines) will contribute to a better understanding of their pathophysiology, which could lead to new approaches to predict, prevent and treat this serious complication of chemotherapy. [Working hypothesis]: Based on two premises: (i) anthracyclines have a pro-genotoxicity effect. Differences in anti-genotoxicity pathways and genetic variants could contribute to different susceptibility to CDA. (ii) The usefulness of a simplified model system to identify genetic determinants involved in the quantitative inheritance of complex traits. [Materials and methods]: We treated a cohort of mice carrying ERBB2 breast cancer with doxorubicin alone (N = 85) or in combination with docetaxel (N = 77). The cohort was generated by a backcross between two genetically homogeneous strains, C57BL/6 and FVB, with the latter carrying the MMTV- ErbB2 / Neu transgene. Histopathologic heart damage was assessed by quantification of histologic parameters using Ariol automated system. Cardiac level of some key anti-genotoxicity proteins: ATR total, pp53 (Ser15), P21 Total, Total MDM2, pHistone H2AX (Ser139), pCHK1 (Ser345) and pCHK2 (Thr68) were quantified. [Results]: We identified: (i) differences dependent on the genetic background in both cardiotoxicity and the levels of proteins implicated in the pathways protecting against genotoxicity; (ii) activation of anti-genotoxicity pathways were associated with chemotherapy cardiotoxicity; (iii) quantitative trait loci (QTLs) specific and common to cardiotoxicity and the levels of the pathways studied. [Conclusion]: We identified genetic determinants associated with anthracycline cardiotoxicity using components of the anti-genotoxic pathways as subphenotypes. Crosses of syngeneic mouse strains are useful in these studies, but require further validation in the human population.

Published
2016

13. Detección de la proteína mamoglobina en pacientes colombianos con cáncer de seno

Author

Galvis Jiménez, Julie Milena and Ramírez-Clavijo, Sandra

Subjects
Ensayo Inmunoabsorbente Ligado a Enzima (ELISA), Mamoglobina, Diagnostico [Neoplasmas de la mama], Investigaciones [Cáncer], Genética, Oncología
Abstract

Entre los años 2003 y 2004, según datos recolectados por el Instituto Nacional de Cancerología (INC) de Bogotá, hubo un incremento del 13% de los casos de cáncer registrados, siendo el de seno el segundo más frecuente en la población colombiana femenina. La principal prueba de tamizaje utilizada para detectar la aparición de lesiones mamarias malignas es la mamografía, pero su sensibilidad puede variar entre el 68 y el 90% (Diaz, et al., 2005). Algunos estudios han postulado como un candidato a marcador celular para el diagnóstico y seguimiento a la glicoproteína Mamoglobina humana que se expresa de manera específica en la glándula mamaria y se sobre-expresa en la mayoría de los tumores primarios y metastásico de pacientes con cáncer de seno (Fleming, et al., 2000). Desde el año 1996 cuando se identificó la Mamoglobina varios autores han reportado la especificidad de la expresión de esta proteína hacía la glándula mamaria a través de estudios de RT-PCR e inmunohistoquímica analizando muestras de tejido normal y tumoral (Watson, et al, 1996; Watson, et al, 1999; Suchy, et al, 2000; O`Brien, et al, 2002; Zehentner, et al, 2004). La Mamoglobina humana por ser una glicoproteína secretada por las células de la glándula mamaria, sobre-expresada en células tumorales y presente en el suero de mujeres con o sin cáncer, se ha identificado como un posible candidato para marcador tumoral celular sérico (Fanger, et al, 2002; Bernstein, et al., 2005; Zehentner, et al., 2004). Este estudio evaluó la presencia de la proteína Mamoglobina en muestras de suero de pacientes con cáncer de seno, estableció la concentración de esta y la comparó con un grupo control constituido por personas sin ningún tipo de cáncer, mediante el Ensayo Inmunoabsorbente Ligado a Enzima. FIUR

Published
2011
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15. Intermediate molecular phenotypes to identify genetic markers of anthracycline-induced cardiotoxicity risk.

Author

Gómez-Vecino A, Corchado-Cobos R, Blanco-Gómez A, García-Sancha N, Castillo-Lluva S, Martín-García A, Mendiburu-Eliçabe M, Prieto C, Ruiz-Pinto S, Pita G, Velasco-Ruiz A, Patino-Alonso C, Galindo-Villardón P, Vera-Pedrosa ML, Jalife J, Mao JH, de Plasencia GM, Castellanos-Martín A, Freire MDMS, Fraile-Martín S, Rodrigues-Teixeira T, García-Macías C, Galvis-Jiménez JM, García-Sánchez A, Isidoro-García M, Fuentes M, García-Cenador MB, García-Criado FJ, García JL, Hernández-García MÁ, Hernández JJC, Rodríguez-Sánchez CA, Martín-Ruiz A, Pérez-López E, Pérez-Martínez A, Gutiérrez-Larraya F, Cartón AJ, García-Sáenz JÁ, Patiño-García A, Martín M, Gordoa TA, Vulsteke C, Croes L, Hatse S, Brussel TV, Lambrechts D, Wildiers H, Hang C, Holgado-Madruga M, González-Neira A, Sánchez PL, and Losada JP

Abstract

Cardiotoxicity due to anthracyclines (CDA) affects cancer patients, but we cannot predict who may suffer from this complication. CDA is a complex disease whose polygenic component is mainly unidentified. We propose that levels of intermediate molecular phenotypes in the myocardium associated with histopathological damage could explain CDA susceptibility; so that variants of genes encoding these intermediate molecular phenotypes could identify patients susceptible to this complication. A genetically heterogeneous cohort of mice generated by backcrossing (N = 165) was treated with doxorubicin and docetaxel. Cardiac histopathological damage was measured by fibrosis and cardiomyocyte size by an Ariol slide scanner. We determine intramyocardial levels of intermediate molecular phenotypes of CDA associated with histopathological damage and quantitative trait loci (ipQTLs) linked to them. These ipQTLs seem to contribute to the missing heritability of CDA because they improve the heritability explained by QTL directly linked to CDA (cda-QTLs) through genetic models. Genes encoding these molecular subphenotypes were evaluated as genetic markers of CDA in three cancer patient cohorts (N = 517) whose cardiac damage was quantified by echocardiography or Cardiac Magnetic Resonance. Many SNPs associated with CDA were found using genetic models. LASSO multivariate regression identified two risk score models, one for pediatric cancer patients and the other for women with breast cancer. Molecular intermediate phenotypes associated with heart damage can identify genetic markers of CDA risk, thereby allowing a more personalized patient management. A similar strategy could be applied to identify genetic markers of other complex trait diseases.

Published
2023
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