DOI: https://doi.org/10.22263/2312-4156.2024.4.37
I.A. Karputs1, V.A. Snezhitskiy1, M.N. Kurbat1, V.A. Harustovich1, A.S. Babenka2
Rare variants of the TTN gene in breast cancer patients with moderate and low cardiovascular risk (HFA-ICOS) during chemotherapy with doxorubicin
1Grodno State Medical University, Grodno, Republic of Belarus
2Belarusian State Medical University, Minsk, Republic of Belarus
Vestnik VGMU. 2024;23(4):37-43.
Abstract.
A study was conducted on 100 patients diagnosed with breast cancer (BC), categorized into low and moderate cardiovascular risk groups against the background of chemotherapy with doxorubicin according to HFA-ICOS criteria. The frequency of rare variants of the TTN gene, associated with the risk of developing dilated cardiomyopathy (DCM), was assessed in patients with BC undergoing chemotherapy (CT) with doxorubicin by means of allele discrimination using real-time PCR. The incidence of rare TTN variants in the studied cohort associated with the development of DCM was 4% (0.7% in the main population). Based on the clinical study data, it can be suggested that the presence of rare TTN variants should be considered as an additional molecular-genetic factor that increases the likelihood of developing DCM in patients with BC undergoing chemotherapy (CT) with doxorubicin categorized into low or moderate risk groups according to HFA-ICOS. Identifying these variants before the commencement of treatment is expected to aid in the timely implementation of preventive measures, thereby decreasing the incidence of DCM during chemotherapy with doxorubicin.
Keywords: anthracyclines, doxorubicin, cardiotoxicity, breast cancer, genes, echocardiography, TTN.
Financing. The research was conducted within the frames of the theme task 3.57 of State Research Programs (GPNI) “Translation Medicine”, subprogram 4.3. “Innovation technologies of clinical medicine” 2020-2025.
References
1. Lyon AR, López-Fernández T, Couch LS, Asteggiano R, Aznar MC, Bergler-Klein J, 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 Nov;43(41):4229-4361. doi: http://dx.doi.org/10.1093/eurheartj/ehac244
2. McGowan JV, Chung R, Maulik A, Piotrowska I, Walker JM, Yellon DM. Anthracycline Chemotherapy and Cardiotoxicity. Cardiovasc Drugs Ther. 2017 Feb;31(1):63-75. doi: http://dx.doi.org/10.1007/s10557-016-6711-0
3. Lyon AR, Dent S, Stanway S, Earl H, Brezden-Masley C, Cohen-Solal A, et al. Baseline cardiovascular risk assessment in cancer patients scheduled to receive cardiotoxic cancer therapies: a position statement and new risk assessment tools from the Cardio-Oncology Study Group of the Heart Failure Association of the European Society of Cardiology in collaboration with the International Cardio-Oncology Society. Eur J Heart Fail. 2020 Nov;22(11):1945-60. doi: http://dx.doi.org/10.1002/ejhf.1920
4. Akhtar MM, Lorenzini M, Cicerchia M, Ochoa JP, Hey TM, Molina MS, et al. Clinical phenotypes and prognosis of dilated cardiomyopathy caused by truncating variants in the TTN gene. Circ Heart Fail. 2020 Oct;13(10):e006832. doi: http://dx.doi.org/10.1161/CIRCHEARTFAILURE.119.006832
5. Schiabor Barrett KM, Cirulli ET, Bolze A, Rowan C, Elhanan G, Grzymski JJ, et al. Cardiomyopathy prevalence exceeds 30% in individuals with TTN variants and early atrial fibrillation. Genet Med. 2023 Apr;25(4):100012. doi: http://dx.doi.org/10.1016/j.gim.2023.100012
6. Curigliano G, Lenihan D, Fradley M, Ganatra S, Barac A, Blaes A, et al. Management of cardiac disease in cancer patients throughout oncological treatment: ESMO consensus recommendations. Ann Oncol. 2020 Feb;31(2):171-90. doi: http://dx.doi.org/10.1016/j.annonc.2019.10.023
7. Yang X, Li G, Yang T, Guan M, An Na, Yang F, et al. Possible susceptibility genes for intervention against chemotherapy-induced cardiotoxicity. Oxid Med Cell Longev. 2020 Oct:2020:4894625. doi: http://dx.doi.org/10.1155/2020/4894625
8. Garcia-Pavia P, Kim Y, Restrepo-Cordoba MA, Lunde IG, Wakimoto H, Smith AM, et al. Genetic variants associated with cancer therapy-induced cardiomyopathy. Circulation. 2019 Jul;140(1):31-41. doi: http://dx.doi.org/10.1161/CIRCULATIONAHA.118.037934
9. Al-Otaibi TK, Weitzman B, Tahir UA, Asnani Aarti. Genetics of anthracycline-associated cardiotoxicity. Front Cardiovasc Med. 2022 Apr:9:867873. doi: http://dx.doi.org/10.3389/fcvm.2022.867873
10. Hinson JT, Chopra A, Nafissi N, Polacheck WJ, Benson CC, Swist S, et al. HEART DISEASE. Titin mutations in iPS cells define sarcomere insufficiency as a cause of dilated cardiomyopathy. Science. 2015 Aug;349(6251):982-6. doi: http://dx.doi.org/10.1126/science.aaa5458
11. Itoh-Satoh M, Hayashi T, Nishi H, Koga Y, Arimura T, Koyanagi T, et al. Titin mutations as the molecular basis for dilated cardiomyopathy. Biochem Biophys Res Commun. 2002 Feb;291(2):385-93. doi: http://dx.doi.org/10.1006/bbrc.2002.6448
12. Herman DS, Lam L, Taylor MRG, Wang L, Teekakirikul P, Christodoulou D, et al. Truncations of titin causing dilated cardiomyopathy. N Engl J Med. 2012 Feb;366(7):619-28. doi: http://dx.doi.org/10.1056/NEJMoa1110186
13. Hackman P, Vihola A, Haravuori H, Marchand S, Sarparanta J, De Seze J, et al. Tibial muscular dystrophy is a titinopathy caused by mutations in TTN, the gene encoding the giant skeletal-muscle protein titin. Am J Hum Genet. 2002 Sep;71(3):492-500. doi: http://dx.doi.org/10.1086/342380
14. Evilä A, Vihola A, Sarparanta J, Raheem O, Palmio J, Sandell S, et al. Atypical phenotypes in titinopathies explained by second titin mutations. Ann Neurol. 2014 Feb;75(2):230-40. doi: http://dx.doi.org/10.1002/ana.24102
15. Jolfayi AG, Kohansal E, Ghasemi S, Naderi N, Hesami M, Bazargany MHM, et al. TTN variants as genetic insights into cardiomyopathy pathogenesis and potential emerging clues to molecular mechanisms in cardiomyopathies. Sci Rep. 2024 Mar;14(1):5313. doi: http://dx.doi.org/10.1038/s41598-024-56154-7
Submitted 28.06.2024
Accepted 28.08.2024
Information about authors:
I.A. Karputs – postgraduate of the Chair of Internal Diseases No. 1, Grodno State Medical University, https://orcid.org/0000-0003-0478-9419,
e-mail: Этот адрес электронной почты защищён от спам-ботов. У вас должен быть включен JavaScript для просмотра. – Irina A. Karputs;
V.A. Snezhitskiy – Doctor of Medical Sciences, corresponding member of the National Academy of Sciences of Belarus, professor of the Chair of Internal Diseases No. 1, Grodno State Medical University, https://orcid.org/0000-0002-1706-1243
M.N. Kurbat – Candidate of Medical Sciences, associate professor, head of the research laboratory, Grodno State Medical University, https://orcid.org/0000-0002-8518-2450
V.A. Harustovich – Candidate of Medical Sciences, associate professor of the Chair of Normal Physiology, Grodno State Medical University, https://orcid.org/0009-0007-3089-8543
A.S. Babenka – Candidate of Chemical Sciences, associate professor of the Chair of General Chemistry, Belarusian State Medical University, https://orcid.org/0000-0002-5513-970Х
