Gómez-Vecino Aurora, Corchado-Cobos Roberto, Blanco-Gómez Adrián, García-Sancha Natalia, Castillo-Lluva Sonia, Martín-García Ana, Mendiburu-Eliçabe Marina, Prieto Carlos, Ruiz-Pinto Sara, Pita Guillermo, Velasco-Ruiz Alejandro, Patino-Alonso Carmen, Galindo-Villardón Purificación, Vera-Pedrosa María Linarejos, Jalife José, Mao Jian-Hua, de Plasencia Guillermo Macías, Castellanos-Martín Andrés, Freire María Del Mar Sáez, Fraile-Martín Susana, Rodrigues-Teixeira Telmo, García-Macías Carmen, Galvis-Jiménez Julie Milena, García-Sánchez Asunción, Isidoro-García María, Fuentes Manuel, García-Cenador María Begoña, García-Criado Francisco Javier, García Juan Luis, Hernández-García María Ángeles, Hernández Juan Jesús Cruz, Rodríguez-Sánchez César Augusto, Martín-Ruiz Alejandro, Pérez-López Estefanía, Pérez-Martínez Antonio, Gutiérrez-Larraya Federico, Cartón Antonio J, García-Sáenz José Ángel, Patiño-García Ana, Martín Miguel, Gordoa Teresa Alonso, Vulsteke Christof, Croes Lieselot, Hatse Sigrid, Brussel Thomas Van, Lambrechts Diether, Wildiers Hans, Hang Chang, Holgado-Madruga Marina, González-Neira Anna, Sánchez Pedro L, Losada Jesús Pérez
Instituto de Biología Molecular y Celular del Cáncer (IBMCC-CIC), Universidad de Salamanca/CSIC, Salamanca, 37007, Spain.
Instituto de Investigación Biosanitaria de Salamanca (IBSAL), Salamanca, 37007, Spain.
bioRxiv. 2023 Jan 6:2023.01.05.522844. doi: 10.1101/2023.01.05.522844.
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.
蒽环类药物所致心脏毒性（CDA）会影响癌症患者，但我们无法预测谁可能会出现这种并发症。CDA是一种复杂疾病，其多基因成分主要尚未明确。我们提出，与组织病理学损伤相关的心肌中间分子表型水平可以解释CDA易感性；因此，编码这些中间分子表型的基因变体可以识别易患这种并发症的患者。通过回交产生的一组基因异质性小鼠（N = 165）接受了多柔比星和多西他赛治疗。通过纤维化测量心脏组织病理学损伤，并使用Ariol玻片扫描仪测量心肌细胞大小。我们确定了与组织病理学损伤相关的CDA心肌内中间分子表型水平以及与之相关的数量性状位点（ipQTLs）。这些ipQTLs似乎有助于解释CDA缺失的遗传力，因为它们通过遗传模型提高了与CDA直接相关的QTL（cda-QTLs）所解释的遗传力。在三个癌症患者队列（N = 517）中，通过超声心动图或心脏磁共振对心脏损伤进行量化，评估了编码这些分子亚表型的基因作为CDA的遗传标记。使用遗传模型发现了许多与CDA相关的单核苷酸多态性。套索多变量回归确定了两个风险评分模型，一个用于儿科癌症患者，另一个用于乳腺癌女性患者。与心脏损伤相关的分子中间表型可以识别CDA风险的遗传标记，从而实现更个性化的患者管理。类似的策略可用于识别其他复杂性状疾病的遗传标记。
