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

被引：1

作者：

Gomez-Vecino, Aurora ^{[1
,2
,10
]}

Corchado-Cobos, Roberto ^{[1
,2
,10
]}

Blanco-Gomez, Adrian ^{[1
,2
,10
]}

Garcia-Sancha, Natalia ^{[1
,2
,10
]}

Castillo-Lluva, Sonia ^{[3
,4
,10
]}

Martin-Garcia, Ana ^{[2
,5
,10
]}

Mendiburu-Elicabe, Marina ^{[1
,2
,10
]}

Prieto, Carlos ^{[6
,10
]}

Ruiz-Pinto, Sara ^{[7
,10
]}

Pita, Guillermo ^{[7
,10
]}

Velasco-Ruiz, Alejandro ^{[7
,10
]}

Patino-Alonso, Carmen ^{[2
,8
,10
]}

Galindo-Villardon, Purificacion ^{[2
,8
,9
,10
]}

Vera-Pedrosa, Maria Linarejos ^{[10
]}

Jalife, Jose ^{[10
]}

Mao, Jian-Hua ^{[10
,11
,12
]}

de Plasencia, Guillermo Macias ^{[2
,5
,10
]}

Castellanos-Martin, Andres ^{[1
,2
,10
]}

Saez-Freire, Maria del Mar ^{[1
,2
,10
]}

Fraile-Martin, Susana ^{[10
,13
]}

Rodrigues-Teixeira, Telmo ^{[10
,13
]}

Garcia-Macias, Carmen ^{[10
,13
]}

Galvis-Jimenez, Julie Milena ^{[1
,2
,10
,14
]}

Garcia-Sanchez, Asuncion ^{[2
,10
,15
]}

Isidoro-Garcia, Maria ^{[2
,10
,15
,16
]}

Fuentes, Manuel ^{[1
,2
,10
,16
,17
]}

Garcia-Cenador, Maria Begona ^{[2
,10
,18
]}

Garcia-Criado, Francisco Javier ^{[2
,10
,18
]}

Garcia-Hernandez, Juan Luis ^{[1
,2
,10
]}

Hernandez-Garcia, Maria Angeles ^{[10
,19
]}

Cruz-Hernandez, Juan Jesus ^{[1
,2
,10
,20
]}

Rodriguez-Sanchez, Cesar Augusto ^{[1
,2
,10
,20
]}

Garcia-Sancho, Alejandro Martin ^{[1
,2
,10
,19
]}

Perez-Lopez, Estefania ^{[1
,2
,10
,19
]}

Perez-Martinez, Antonio ^{[10
,21
]}

Gutierrez-Larraya, Federico ^{[10
,22
]}

Carton, Antonio J. ^{[10
,22
]}

Garcia-Saenz, Jose Angel ^{[10
,23
]}

Patino-Garcia, Ana ^{[10
,24
]}

Martin, Miguel ^{[10
,25
]}

Alonso-Gordoa, Teresa ^{[10
,26
]}

Vulsteke, Christof ^{[10
,27
,28
]}

Croes, Lieselot ^{[10
,27
,28
]}

Hatse, Sigrid ^{[10
,29
]}

Van Brussel, Thomas ^{[10
,30
,31
]}

Lambrechts, Diether ^{[10
,30
,31
]}

Wildiers, Hans ^{[10
,32
,33
,34
,35
]}

Chang, Hang ^{[10
,11
,12
]}

Holgado-Madruga, Marina ^{[2
,10
,36
,37
]}

Gonzalez-Neira, Anna ^{[7
,10
]}

机构：

[1] Univ Salamanca, Inst Biol Mol & Celular Canc IBMCC CIC, CSIC, Salamanca 37007, Spain

[2] Inst Invest Biosanit Salamanca IBSAL, Salamanca 37007, Spain

[3] Univ Complutense, Fac Ciencias Quim, Dept Bioquim & Biol Mol, Madrid 28040, Spain

[4] Inst Invest Sanitarias San Carlos IdISSC, Madrid 24040, Spain

[5] Univ Salamanca CIBERCV, Hosp Univ Salamanca, Serv Cardiol, Salamanca 37007, Spain

[6] Univ Salamanca, Serv Bioinformat Nucl, Salamanca 37007, Spain

[7] Spanish Natl Canc Res Ctr CNIO, Human Canc Genet Programme, Human Genotyping Unit CeGen, Madrid 28029, Spain

[8] Univ Salamanca, Dept Estadist, Salamanca 37007, Spain

[9] Escuela Super Politecn Litoral, ESPOL, Ctr Estudios Invest Estadist, Campus Gustavo Galindo,Km 30-5 Via Perimetral,POB, Guayaquil, Ecuador

[10] Ctr Nacl Invest Cardiovasc CN Carlos III, Madrid 28029, Spain

[11] Lawrence Berkeley Natl Lab, Biol Syst & Engn Div, Berkeley, CA 94720 USA

[12] Lawrence Berkeley Natl Lab, Berkeley Biomed Data Sci Ctr, Berkeley, CA 92720 USA

[13] Univ Salamanca, Serv Patol Mol Comparada, Inst Biol Mol & Celular Canc IBMCC CIC, Salamanca 37007, Spain

[14] Inst Nacl Cancerol Colombia, Bogota 111511110411, Colombia

[15] Hosp Univ Salamanca, Serv Bioquim Clin, Salamanca 37007, Spain

[16] Univ Salamanca, Dept Med, Salamanca 37007, Spain

[17] Univ Salamanca, Serv Gen Citometria Flujo Nucl, Salamanca 37007, Spain

[18] Univ Salamanca, Dept Cirug, Salamanca 37007, Spain

[19] Hosp Univ Salamanca, Serv Hematol, CIBERONC, Salamanca 37007, Spain

[20] Hosp Univ Salamanca, Serv Oncol, Salamanca 37007, Spain

[21] Hosp Univ La Paz, Dept Paediat Hemato Oncol, Madrid 28046, Spain

[22] Hosp Univ La Paz, Dept Paediat Cardiol, Madrid 28046, Spain

[23] Hosp Clin San Carlos, Inst Invest Sanitaria Hosp Clin San Carlos IdISSC, Med Oncol Serv, Madrid 28040, Spain

[24] Univ Navarra, Ctr Invest Med Aplicada CIMA, Dept Pediat, Solid Tumor Program,IdisNA, Pamplona 31008, Spain

[25] Univ Complutense, Gregorio Maranon Hlth Res Inst IISGM, Ctr Invest Biomed Red Oncol CIBERONC, Dept Med, Madrid 28007, Spain

[26] Hosp Univ Ramon & Cajal, Dept Med Oncol, Madrid 28034, Spain

[27] Antwerp Univ, Ctr Oncol Res CORE, Dept Mol Imaging Pathol Radiotherapy & Oncol MIPRO, B-2610 Antwerp, Belgium

[28] AZ Maria Middelares, Integrated Canc Ctr Ghent, Dept Oncol, B-9000 Ghent, Belgium

[29] Katholieke Univ KU Leuven, Univ Hosp Leuven, Leuven Canc Inst, Dept Oncol,Lab Expt Oncol LEO,Dept Gen Med Oncol, B-3000 Leuven, Belgium

[30] VIB, VIB Ctr Canc Biol, B-3000 Leuven, Belgium

[31] Katholieke Univ KU Leuven, Dept Human Genet, Lab Translat Genet, B-3000 Leuven, Belgium

[32] Katholieke Univ KU Leuven, Leuven Canc Inst, Multidisciplinary Breast Unit, B-3000 Leuven, Belgium

[33] Katholieke Univ KU Leuven, Dept Gen Med Oncol, B-3000 Leuven, Belgium

[34] Katholieke Univ KU Leuven, Univ Hosp Leuven, B-3000 Leuven, Belgium

[35] Katholieke Univ KU Leuven, Leuven Canc Inst, Dept Oncol, Lab Expt Oncol LEO, B-3000 Leuven, Belgium

[36] Univ Salamanca, Dept Fisiol & Farmacol, Salamanca 37007, Spain

[37] Inst Neurociencias Castilla & Leon INCyL, Salamanca 37007, Spain

来源：

CELLS | 2023年 / 12卷 / 15期

基金：

美国国家卫生研究院;

关键词：

anthracyclines; cardiotoxicity; complex genetic disease; intermediate molecular phenotypes; quantitative trait loci; EARLY BREAST-CANCER; COMPLEX TRAITS; MISSING HERITABILITY; HUMAN HEART; SUSCEPTIBILITY; TUMOR; CHEMOTHERAPY; EXPRESSION; CARDIOMYOPATHY; ARCHITECTURES;

D O I：

10.3390/cells12151956

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页数：28

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