Titin-Truncating Variants as Genetic Determinants of Chemotherapy-Induced Cardiomyopathy: A Review
DOI:
https://doi.org/10.30701/ijc.2121Keywords:
Titin-truncating variants, Chemotherapy-induced cardiomyopathy, Cardio-oncology, Genetic predisposition, ReviewAbstract
Current risk-prediction models for Cancer Therapy–Related Cardiovascular Toxicity (CTR-CVT) rely predominantly on demographic, diagnostic, and treatment variables, lacking genetic determinants of individual susceptibility. Recent evidence suggests cardiomyopathy-associated genetic variants, particularly Titin-truncating variants (TTNtv), may be significant in CTR-CVT development. This review examines the occurrence and impact of TTNtv in CTR-CVT patients. We conducted a PRISMA-guided review analyzing TTNtv in patients with chemotherapy exposure who developed cardiomyopathy. Literature searches were performed in PubMed and Scopus using keywords: “(cardiomyopathy OR heart failure) AND (chemotherapy OR cancer therapy) AND (Titin OR TTNtv).” Quality assessment employed the Newcastle-Ottawa Scale (NOS) for observational studies and the Joanna Briggs Institute (JBI) criteria for case reports. We included 2 case-control studies and 2 case reports. TTNtv prevalence was significantly higher in chemotherapy-induced cardiomyopathy than in controls: 7.5% versus 0.6-1.1% (multicenter cohort), and 6.5% versus 0% (single-center cohort). There are conflicting results regarding symptom severity and prognosis among those with and without TTNtv mutation. One multicenter case-control study with animal model validation demonstrated that chemotherapy is poorly tolerated in TTNtv carriers. Chemotherapy-to-symptom onset ranged from 0.4 to 9 years and primarily involved anthracyclines. Among truncating variations found in the included literature, localization in the A-band of the titin protein predominated. TTNtv represents a predominant genetic determinant in CTR-CVT susceptibility, although its association with severity and recovery outcomes remains inconsistent across studies. Genetic screening could identify high-risk cancer patients benefiting from personalized cardioprotective strategies and enable assessment of prophylactic interventions. Future investigations will determine if early genetic risk recognition optimizes cancer and cardiovascular treatments, potentially transforming precision cardio-oncology care. However, cost-benefit analysis, validation in diverse populations, and comparison with non-anthracycline CTR-CVT groups are needed.
Downloads
References
1. Magavern EF, Kaski JC, Turner RM, et al. The role of pharmacogenomics in contemporary cardiovascular therapy: A position statement from the European Society of Cardiology Working Group on Cardiovascular Pharmacotherapy. Eur Heart J Cardiovasc Pharmacother. Oxford University Press. 2022;8(1):85-99. doi:10.1093/ehjcvp/pvab018
2. Hershberger RE, Cowan J, Jordan E, Kinnamon DD. The Complex and Diverse Genetic Architecture of Dilated Cardiomyopathy. Circ Res. 2021;128(10):1514-1532. doi:10.1161/CIRCRESAHA.121.318157
3. Khan RS, Pahl E, Dellefave-Castillo L, et al. Genotype and Cardiac Outcomes in Pediatric Dilated Cardiomyopathy. J Am Heart Assoc. 2022;11(1). doi:10.1161/JAHA.121.022854
4. Lyon AR, López-Fernánde T, Couch LS, et al. 2022 ESC Guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS). Eur Heart J. 2022;43(41):4229-4361. doi:10.1093/eurheartj/ehac244
5. Yin G, Liu L, Yu T, et al. Genomic and transcriptomic analysis of breast cancer identifies novel signatures associated with response to neoadjuvant chemotherapy. Genome Med. 2024;16(1). doi:10.1186/s13073-024-01286-8
6. Chaix MA, Parmar N, Kinnear C, et al. Machine Learning Identifies Clinical and Genetic Factors Associated With Anthracycline Cardiotoxicity in Pediatric Cancer Survivors. JACC CardioOncol. 2020;2(5):690-706. doi:10.1016/j.jaccao.2020.11.004
7. Garcia-Pavia P, Kim Y, Restrepo-Cordoba MA, et al. Genetic Variants Associated With Cancer Therapy-Induced Cardiomyopathy. Circulation. 2019;140(1):31-41. doi:10.1161/CIRCULATIONAHA.118.037934
8. Boen HM, Alaerts M, Goovaerts I, et al. Variants in structural cardiac genes in patients with cancer therapy-related cardiac dysfunction after anthracycline chemotherapy: a case control study. Cardio-Oncology. 2024;10(1). doi:10.1186/s40959-024-00231-3
9. Linschoten M, Teske AJ, Baas AF, et al. Truncating Titin (TTN) Variants in Chemotherapy-Induced Cardiomyopathy. J Card Fail. 2017;23(6):476-479. doi:10.1016/j.cardfail.2017.03.003
10. Chang YW, Weng HY, Tsai SF, Fan FS. Disclosing an In-Frame Deletion of the Titin Gene as the Possible Predisposing Factor of Anthracycline-Induced Cardiomyopathy: A Case Report. Int J Mol Sci. 2022;23(16). doi:10.3390/ijms23169261
11. Herman DS, Lam L, Taylor MRG, et al. Truncations of Titin Causing Dilated Cardiomyopathy. Vol 366. 2012. www.uniprot.org
12. Ghahremani S, Kanwal A, Pettinato A, et al. CRISPR Activation Reverses Haploinsufficiency and Functional Deficits Caused by TTN Truncation Variants. Circulation. 2024;149(16):1285-1297. doi:10.1161/CIRCULATIONAHA.123.063972
13. Santiago CF, Huttner IG, Fatkin D. Titin-related Cardiomyopathy: Is it a Distinct Disease? Curr Cardiol Rep. Springer. 2022;24(9):1069-1075. doi:10.1007/s11886-022-01726-0
14. Romano R, Ghahremani S, Zimmerman T, et al. Reading Frame Repair of TTN Truncation Variants Restores Titin Quantity and Functions. Circulation. 2022;145(3):194-205. doi:10.1161/CIRCULATIONAHA.120.049997
15. Schafer S, De Marvao A, Adami E, et al. Titin-truncating variants affect heart function in disease cohorts and the general population. Nat Genet. 2017;49(1):46-53.
16. Kim Y gon, Ha C, Shin S, Park J ho, Jang JH, Kim JW. Enrichment of titin-truncating variants in exon 327 in dilated cardiomyopathy and its relevance to reduced nonsense-mediated mRNA decay efficiency. Front Genet. 2023;13:1087359.
17. Linschoten M, Teske AJ, Cramer MJ, Van Der Wall E, Asselbergs FW. Chemotherapy-Related Cardiac Dysfunction: A Systematic Review of Genetic Variants Modulating Individual Risk. Circ Genom Precis Med. Lippincott Williams and Wilkins. 2018;11(1):E001753. doi:10.1161/CIRCGEN.117.001753
18. Chong JH, Chuah CTH, Lee CG. Revolutionising Cardio-Oncology Care with Precision Genomics. Int J Mol Sci. Multidisciplinary Digital Publishing Institute (MDPI). 2025;26(5). doi:10.3390/ijms26052052
19. Leong DP, Waliany S, Abdel-Qadir H, et al. Cardiovascular Considerations During Cancer Therapy: Gaps in Evidence and JACC: CardioOncology Expert Panel Recommendations. JACC CardioOncol. Elsevier Inc. 2024;6(6):815-834. doi:10.1016/j.jaccao.2024.06.005
20. Neupane A, Petrykey K, Li K, et al. TTN and BAG3 in Cancer Therapy–Related Cardiomyopathy Among Long-Term Survivors of Childhood Cancer. JAMA Netw Open. 2025;8(6):e2515793.
21. Serie DJ, Crook JE, Necela BM, et al. Breast cancer clinical trial of chemotherapy and trastuzumab: Potential tool to identify cardiac modifying variants of dilated cardiomyopathy. J Cardiovasc Dev Dis. 2017;4(2):6.
22. Bang ML, Centner T, Fornoff F, et al. The complete gene sequence of titin, expression of an unusual ?700-kDa titin isoform, and its interaction with obscurin identify a novel Z-line to I-band linking system. Circ Res. Lippincott Williams and Wilkins. 2001;89(11):1065-1072. doi:10.1161/hh2301.100981
23. Chauveau C, Rowell J, Ferreiro A. A rising titan: TTN review and mutation update. Hum Mutat. 2014;35(9):1046-1059. doi:10.1002/humu.22611
24. Perrin A, Van Goethem C, Thèze C, et al. Long-Reads Sequencing Strategy to Localize Variants in TTN Repeated Domains. Journal of Molecular Diagnostics. 2022;24(7):719-726. doi:10.1016/j.jmoldx.2022.04.006
25. Aminkeng F, Bhavsar AP, Visscher H, et al. A coding variant in RARG confers susceptibility to anthracycline-induced cardiotoxicity in childhood cancer. Nat Genet. 2015;47(9):1079-1084.
26. Visscher H, Ross CJD, Rassekh SR, et al. Pharmacogenomic prediction of anthracycline-induced cardiotoxicity in children. Journal of clinical oncology. 2012;30(13):1422-1428.
27. Martínez-Campelo L, Blanco-Verea A, López-Fernández T, et al. Meta-analysis of genome-wide association studies for cancer therapy-related cardiovascular dysfunction and functional mapping highlight an intergenic region close to TP63. Sci Rep. 2024;14(1). doi:10.1038/s41598-024-69064-5
28. Ravkin HD, Givton O, Geffen DB, Rubin E. Direct comparison shows that mRNA-based diagnostics incorporate information which cannot be learned directly from genomic mutations. BMC Bioinformatics. 2020;21(1). doi:10.1186/s12859-020-3512-z
29. Leger KJ, Leonard D, Nielson D, de Lemos JA, Mammen PPA, Winick NJ. Circulating microRNAs: Potential Markers of Cardiotoxicity in Children and Young Adults Treated With Anthracycline Chemotherapy. J Am Heart Assoc. 2017;6(4). doi:10.1161/JAHA.116.004653
30. Oatmen KE, Toro-Salazar OH, Hauser K, et al. Identification of a novel microRNA profile in pediatric patients with cancer treated with anthracycline chemotherapy. Am J Physiol Heart Circ Physiol. 2018;315:1443-1452. doi:10.1152/ajpheart.00252.2018.-Anthracycline
31. Roberts AM, Ware JS, Herman DS, et al. Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease. Sci Transl Med. 2015;7(270):270ra6-270ra6. doi:10.1126/scitranslmed.3010134
32. Albini A, Pennesi G, Donatelli F, Cammarota R, De Flora S, Noonan DM. Cardiotoxicity of anticancer drugs: The need for cardio-oncology and cardio-oncological prevention. J Natl Cancer Inst. 2010;102(1):14-25. doi:10.1093/jnci/djp440
33. Emiliani FE, Ismail AAO, Hughes EG, Tsongalis GJ, Zanazzi GJ, Lin CC. Nanopore-based random genomic sampling for intraoperative molecular diagnosis. Genome Med. 2025;17(1). doi:10.1186/s13073-025-01427-7
34. Deacon S, Cahyani I, Holmes N, et al. ROBIN: A unified nanopore-based assay integrating intraoperative methylome classification and next-day comprehensive profiling for ultra-rapid tumor diagnosis. Neuro Oncol. 2025;27(8):2035-2046. doi:10.1093/neuonc/noaf103
35. Iams WT, Mackay M, Ben-Shachar R, et al. Concurrent Tissue and Circulating Tumor DNA Molecular Profiling to Detect Guideline-Based Targeted Mutations in a Multicancer Cohort. JAMA Netw Open. 2024;7(1). doi:10.1001/jamanetworkopen.2023.51700
36. Gimeno-Valiente F, Martín-Arana J, Tébar-Martínez R, et al. Sequencing paired tumor DNA and white blood cells improves circulating tumor DNA tracking and detects pathogenic germline variants in localized colon cancer. ESMO Open. 2023;8(6). doi:10.1016/j.esmoop.2023.102051
37. Uapinyoying P, Goecks J, Knoblac SM, et al. A long-read RNA-seq approach to identify novel transcripts of very large genes. Genome Res. 2020;30(6):885-897. doi:10.1101/gr.259903.119
38. Tekola-Ayele F, Rotimi CN. Translational genomics in low-and middle-income countries: opportunities and challenges. Public Health Genomics. 2015;18(4):242-247.
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2026 Indonesian Journal of Cardiology
This work is licensed under a Creative Commons Attribution 4.0 International License.
Authors who publish with this journal agree to the following terms:
- Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution License that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.
- Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal.
- Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (See The Effect of Open Access).
