Machine learning model identifies genetic predictors of cisplatin-induced ototoxicity in CERS6 and TLR4

被引：1

作者：

Arab, Ali ^{[1
]}

Kashani, Bahareh ^{[2
,3
]}

Cordova-Delgado, Miguel ^{[3
]}

Scott, Erika N. ^{[3
,4
]}

Alemi, Kaveh ^{[1
]}

Trueman, Jessica ^{[3
,4
]}

Groeneweg, Gabriella ^{[4
,5
]}

Chang, Wan-Chun ^{[3
,4
]}

Loucks, Catrina M. ^{[3
,4
,6
]}

Ross, Colin J.D. ^{[3
,7
]}

Carleton, Bruce C. ^{[3
,4
,5
]}

Ester, Martin ^{[1
]}

机构：

[1] School of Computing Science, Simon Fraser University, Burnaby, BC

[2] Department of Experimental Medicine, Faculty of Medicine, University of British Columbia, Vancouver, BC

[3] BC Children's Hospital Research Institute, Vancouver, BC

[4] Division of Translational Therapeutics, Department of Pediatrics, Faculty of Medicine, University of British Columbia, Vancouver, BC

[5] Pharmaceutical Outcomes Programme, BC Children's Hospital, Vancouver, BC

[6] Department of Anesthesiology, Pharmacology & Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, BC

[7] Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC

来源：

Computers in Biology and Medicine | 2024年 / 183卷

基金：

加拿大健康研究院;

关键词：

Adverse drug reaction; Cisplatin; Deep learning; Machine learning; Ototoxicity; Pharmacogenomics;

D O I：

10.1016/j.compbiomed.2024.109324

中图分类号：

学科分类号：

摘要：

Background: Cisplatin-induced ototoxicity remains a significant concern in pediatric cancer treatment due to its permanent impact on quality of life. Previously, genetic association analyses have been performed to detect genetic variants associated with this adverse reaction. Methods: In this study, a combination of interpretable neural networks and Generative Adversarial Networks (GANs) was employed to identify genetic markers associated with cisplatin-induced ototoxicity. The applied method, BRI-Net, incorporates biological domain knowledge to define the network structure and employs adversarial training to learn an unbiased representation of the data, which is robust to known confounders. Leveraging genomic data from a cohort of 362 cisplatin-treated pediatric cancer patients recruited by the CPNDS (Canadian Pharmacogenomics Network for Drug Safety), this model revealed two statistically significant single nucleotide polymorphisms to be associated with cisplatin-induced ototoxicity. Results: Two markers within the CERS6 (rs13022792, p-value: 3 × 10−4) and TLR4 (rs10759932, p-value: 7 × 10−4) genes were associated with this cisplatin-induced adverse reaction. CERS6, a ceramide synthase, contributes to elevated ceramide levels, a known initiator of apoptotic signals in mouse models of inner ear hair cells. TLR4, a pattern-recognition protein, initiates inflammation in response to cisplatin, and reduced TLR4 expression has been shown in murine hair cells to confer protection from ototoxicity. Conclusion: Overall, these findings provide a foundation for understanding the genetic landscape of cisplatin-induced ototoxicity, with implications for improving patient care and treatment outcomes. © 2024 The Authors

引用

共 90 条

[1] Yancey A., Harris M.S., Egbelakin A., Gilbert J., Pisoni D.B., Renbarger J., Risk factors for cisplatin‐associated ototoxicity in pediatric oncology patients, Pediatr. Blood Cancer, 59, 1, pp. 144-148, (2012)
[2] Wang X., Zhou Y., Wang D., Wang Y., Zhou Z., Ma X., Et al., Cisplatin-induced ototoxicity: from signaling network to therapeutic targets, Biomed. Pharmacother., 157, (2023)
[3] Chattaraj A., Syed M.P., Low C.A., Owonikoko T.K., Cisplatin-induced ototoxicity: a concise review of the burden, prevention, and interception strategies, JCO Oncology Practice, 19, 5, pp. 278-283, (2023)
[4] Knight K.R.G., Kraemer D.F., Neuwelt E.A., Ototoxicity in children receiving platinum chemotherapy: underestimating a commonly occurring toxicity that may influence academic and social development, J. Clin. Oncol., 23, 34, pp. 8588-8596, (2005)
[5] Goutman J.D., Elgoyhen A.B., Gomez-Casati M.E., Cochlear hair cells: the sound-sensing machines, FEBS (Fed. Eur. Biochem. Soc.) Lett., 589, 22, pp. 3354-3361, (2015)
[6] Kishimoto-Urata M., Urata S., Fujimoto C., Yamasoba T., Role of oxidative stress and antioxidants in acquired inner ear disorders, Antioxidants, 11, 8, (2022)
[7] Marullo R., Werner E., Degtyareva N., Moore B., Altavilla G., Ramalingam S.S., Et al., Cisplatin induces a mitochondrial-ROS response that contributes to cytotoxicity depending on mitochondrial redox status and bioenergetic functions, PLoS One, 8, 11, (2013)
[8] Domingo I.K., Latif A., Bhavsar A.P., Pro-inflammatory signalling PRRopels cisplatin-induced toxicity, Int. J. Mol. Sci., 23, 13, (2022)
[9] Scott E.N., Joseph A.A., Dhanda A., Tanoshima R., Brooks B., Rassekh S.R., Et al.
[10] Peters U., Preisler-Adams S., Hebeisen A., Hahn M., Seifert E., Lanvers C., Et al., Glutathione S-transferase genetic polymorphisms and individual sensitivity to the ototoxic effect of cisplatin, Anti Cancer Drugs, 11, 8, pp. 639-643, (2000)

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