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Published on: October 26, 2020
Exploring an novel diagnostic gene of trastuzumab-induced cardiotoxicity based on bioinformatics and machine learning
Jixiang Pei1, Luxin Feng2, Qiang Mu3
1Department of Cardiology, Qingdao Central Hospital, University of Health and Rehabilitation Sciences, Qingdao, China.
Abstract:
Trastuzumab (Tra)-induced cardiotoxicity (TIC) is a serious side effect of cancer chemotherapy, which can seriously harm the health of cancer patients. However, there is currently a lack of effective and reliable biomarkers for the early diagnosis of TIC in clinical practice. Therefore, we screened the TIC candidate diagnostic gene solute carrier family 6 member 6 (SLC6A6) by combining multi-machine learning algorithm based on bioinformatics. In addition, cross-validation showed that SLC6A6 had a consistent expression trend in multi-data-sets. To further explore the diagnostic capability of SLC6A6 in TIC, we constructed a nomogram diagnostic model based on SLC6A6 expression level, and receiver operating characteristic (ROC) curve, calibration curve and decision curve analysis proved that SLC6A6 had good diagnostic capability. In order to further verify the TIC expression of SLC6A6 in the real world, we have constructed cell and animal models. Animal experiments showed that left ventricular ejection fraction (LVEF) was significantly decreased (from 65.01 ± 3.30% and 351.32 ± 3.51%, p < 0.0001) after Tra injection, and severe cardiac function was impaired. Similarly, RT-QPCR demonstrated that SLC6A6 was significantly downregulated in Tra-treated cardiomyocytes in vitro and in vivo. Our study suggests that the differential expression of SLC6A6 in vitro and in vivo models is associated with TIC, which may be a candidate diagnostic gene for the early occurrence and development of TIC and a potential therapeutic target.
Insights
Solute carrier family 6 member 6 (SLC6A6) may serve as an early diagnostic biomarker for Trastuzumab-induced cardiotoxicity (TIC). This study identified SLC6A6 downregulation in cardiac models, suggesting its potential for early TIC detection and treatment.
Area of Science:
- Oncology
- Cardiology
- Genetics
- Bioinformatics
Background:
- Trastuzumab-induced cardiotoxicity (TIC) is a significant clinical challenge in cancer therapy.
- Current diagnostic methods for TIC lack effective and reliable early biomarkers.
- Early detection of TIC is crucial for patient management and preventing severe cardiac damage.
Purpose of the Study:
- To identify novel candidate diagnostic genes for Trastuzumab-induced cardiotoxicity (TIC).
- To evaluate the diagnostic capability of solute carrier family 6 member 6 (SLC6A6) in TIC.
- To explore SLC6A6 as a potential therapeutic target for TIC.
Main Methods:
- Bioinformatic analysis integrating multi-machine learning algorithms to screen for TIC candidate genes.
- Cross-validation of SLC6A6 expression trends across multiple datasets.
- Construction of a nomogram diagnostic model using SLC6A6 expression levels, validated by ROC curves, calibration, and decision curve analyses.
- In vitro and in vivo validation using cell and animal models of TIC, including RT-qPCR and assessment of left ventricular ejection fraction (LVEF).
Main Results:
- SLC6A6 was identified as a candidate diagnostic gene for TIC through bioinformatics screening.
- SLC6A6 demonstrated consistent expression trends across datasets and good diagnostic capability in the nomogram model.
- Animal models showed significantly decreased LVEF after Trastuzumab treatment, indicating severe cardiac impairment.
- SLC6A6 was significantly downregulated in Trastuzumab-treated cardiomyocytes both in vitro and in vivo.
Conclusions:
- The differential expression of SLC6A6 is associated with Trastuzumab-induced cardiotoxicity.
- SLC6A6 shows promise as a candidate diagnostic gene for the early detection of TIC.
- SLC6A6 may represent a potential therapeutic target for mitigating TIC.
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