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Clinical, cellular, and molecular characterisation of cardiac rhabdomyoma in tuberous sclerosis

Part of: Surgery

Published online by Cambridge University Press:  19 February 2021

Hamood N. Al Kindi Open the ORCID record for Hamood N. Al Kindi [Opens in a new window] ,
Ayman M. Ibrahim ,
Mohamed Roshdy ,
Besra S. Abdelghany ,
Dina Yehia ,
Ahmed Nageeb Masoud ,
Walid Simry ,
Yasmine Aguib  and
Magdi H. Yacoub
Hamood N. Al Kindi
Affiliation:
Aswan Heart Center, Aswan, Egypt Department of Cardiothoracic Surgery, Sultan Qaboos University Hospital, Muscat, Sultanate of Oman
Ayman M. Ibrahim
Affiliation:
Aswan Heart Center, Aswan, Egypt Department of Zoology, Faculty of Science, Cairo University, Giza, Egypt
Mohamed Roshdy
Affiliation:
Aswan Heart Center, Aswan, Egypt
Besra S. Abdelghany
Affiliation:
Aswan Heart Center, Aswan, Egypt
Dina Yehia
Affiliation:
Aswan Heart Center, Aswan, Egypt
Ahmed Nageeb Masoud
Affiliation:
Aswan Heart Center, Aswan, Egypt
Walid Simry
Affiliation:
Aswan Heart Center, Aswan, Egypt
Yasmine Aguib
Affiliation:
Aswan Heart Center, Aswan, Egypt National Heart and Lung Institute, Imperial College London, London, UK
Magdi H. Yacoub*
Affiliation:
Aswan Heart Center, Aswan, Egypt National Heart and Lung Institute, Imperial College London, London, UK Heart Science Centre, Harefield Hospital, London, UK
*
Author for correspondence: Prof Magdi Yacoub FRS, Heart Science Centre, National Heart and Lung Institute, Imperial College London, London, UK. Tel: +44 (0)1895 828 893. E-mail: m.yacoub@imperial.ac.uk
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Abstract

Background:

Rhabdomyoma is the most common cardiac tumour in children. It is usually associated with tuberous sclerosis complex caused by mutations in TSC-1 or TSC-2 genes. This tumour typically regresses by unknown mechanisms; however, it may cause inflow or outflow obstruction that necessitates urgent surgery. Here we investigate the clinical features and the genetic analysis of patients with tuberous sclerosis complex presenting with large rhabdomyoma tumours. We also investigate the potential role of autophagy and apoptosis in the pathogenesis of this tumour.

Methods:

All the patients with cardiac rhabdomyoma referred to Aswan Heart Centre from 2010 to 2018 were included in this study. Sanger sequencing was performed for coding exons and the flanking intronic regions of TSC1 and TSC2 genes. Histopathological evaluation, immunohistochemistry, and western blotting were performed with P62, LC3b, caspase3, and caspase7, to evaluate autophagic and apoptotic signaling.

Results:

Five patients were included and had the clinical features of tuberous sclerosis complex. Three patients, who were having obstructive tumours, were found to have pathogenic mutations in TSC-2. The expression of two autophagic markers, P62 and LC3b, and two apoptotic markers, caspase3 and caspase7, were increased in the tumour cells compared to normal surrounding myocardial tissue.

Conclusion:

All the patients with rhabdomyoma were diagnosed to have tuberous sclerosis complex. The patients who had pathogenic mutations in the TSC-2 gene had a severe disease form necessitating urgent intervention. We also demonstrate the potential role of autophagy and apoptosis as a possible mechanism for tumourigenesis and regression. Future studies will help in designing personalised treatment for cardiac rhabdomyoma.

Keywords

Cardiac rhabdomyomatuberous sclerosis (TSC)tuberous sclerosis complex-1 (TSC-1)tuberous sclerosis complex-2 (TSC-2)mammalian target of rapamycin (mTOR) pathwayautophagyapoptosis
Type
Original Article
Information
Cardiology in the Young , Volume 31 , Issue 8 , August 2021 , pp. 1297 - 1305
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Copyright
© The Author(s), 2021. Published by Cambridge University Press

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References

Elderkin, RA, Radford, DJ. Primary cardiac tumours in a paediatric population. J Paediatr Child Health 2002; 38: 173–177.CrossRefGoogle Scholar
Padalino, MA, Reffo, E, Cerutti, A, et al. Medical and surgical management of primary cardiac tumours in infants and children. Cardiol Young 2008; 24: 268–274.CrossRefGoogle Scholar
Kwiatkowska, J, Wałdoch, A, Meyer-Szary, J, Potaz, P, Grzybiak, M, Cardiac tumors in children: a 20-year review of clinical presentation, diagnostics and treatment. Adv Clin Exp Med 2017; 26: 319–326.CrossRefGoogle ScholarPubMed
Padalino, MA, Vida, V, Boccuzzo, G, et al., Surgery for primary cardiac tumors in children early and late results in a multicenter european congenital heart surgeons association study. Circulation 2012; 126: 22–30.CrossRefGoogle Scholar
Beaird, J, Mowry, RW, Cunningham, JA. Congenital rhabdomyoma of the heart. Case report with histochemical study of tumor polysaccharide. Cancer 1955; 8: 916–920.3.0.CO;2-6>CrossRefGoogle ScholarPubMed
Labate, JS. Congenital rhabdomyoma of the heart: report of a case – PubMed. Am J Pathol 1939; 15: 137–150.1.Google Scholar
Rae, MV, Congenital rhabdomyoma of the heart – PubMed. Can Med Assoc J 1938; 39: 63–64.Google Scholar
Harding, CO, Pagon, RA. Incidence of tuberous sclerosis in patients with cardiac rhabdomyoma. Am J Med Genet 1990; 37: 443–446.CrossRefGoogle ScholarPubMed
Crino, PB, Nathanson, KL, Henske, EP. Medical progress: the tuberous sclerosis complex. N Engl J Med 2006; 355: 1345–1356.CrossRefGoogle Scholar
Manning, BD. Game of TOR — The target of rapamycin rules four kingdoms. N Engl J Med 2017; 377: 1297–1299.CrossRefGoogle ScholarPubMed
Kotulska, K, Larysz-Brysz, M, Grajkowska, W, et al. Cardiac rhabdomyomas in tuberous sclerosis complex show apoptosis regulation and mTOR pathway abnormalities. Pediatr Dev Pathol: Off J Soc Pediatr Pathol Paediatr Pathol Soc 2009; 12: 89–95.CrossRefGoogle ScholarPubMed
Aw, F, Goyer, I, Raboisson, MJ, Boutin, C, Major, P, Dahdah, N. Accelerated cardiac rhabdomyoma regression with everolimus in infants with tuberous sclerosis complex. Pediatr Cardiol 2017; 38: 394–400.CrossRefGoogle ScholarPubMed
Avgeris, S, Fostira, F, Vagena, A, et al., Mutational analysis of TSC1 and TSC2 genes in Tuberous Sclerosis Complex patients from Greece. Sci Rep 2017; 7: 1–9.CrossRefGoogle ScholarPubMed
Rosset, C, Vairo, F, Bandeira, IC, et al., Molecular analysis of TSC1 and TSC2 genes and phenotypic correlations in Brazilian families with tuberous sclerosis. PLoS One 2017; 12: e0185713.CrossRefGoogle ScholarPubMed
Richards, S, Aziz, N, Bale, S, et al., Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17: 405–423.CrossRefGoogle ScholarPubMed
Nykamp, K, Anderson, M, Powers, M, et al., Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. Genet Med 2017; 19: 1105–1117.CrossRefGoogle ScholarPubMed
Saxton, RA, Sabatini, DM. mTOR signaling in growth, metabolism, and disease. Cell 2017; 168: 960–976.CrossRefGoogle Scholar
Dabora, SL, Jozwiak, S, Franz, DN, et al., Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs. Am J Hum Genet 2001; 68: 64–80.CrossRefGoogle Scholar
Rosset, C, Netto, CBO, Ashton-Prolla, P. TSC1 and TSC2 gene mutations and their implications for treatment in tuberous sclerosis complex: a review. Genet Mol Biol 2017; 40: 69–79.CrossRefGoogle ScholarPubMed
Castro, AF, Rebhun, JF, Clark, GJ, Quilliam, LA. Rheb binds tuberous sclerosis complex 2 (TSC2) and promotes S6 kinase activation in a rapamycin- and farnesylation-dependent manner. J Biol Chem 2003; 278: 32493–32496.CrossRefGoogle Scholar
Milano, EG, Prioli, MA, Vassanelli, C. Spontaneous regression of a large rhabdomyoma of the interventricular septum. Cardiol Young 2008; 24: 379–381.CrossRefGoogle Scholar
Dunlop, EA, Tee, AR. MTOR and autophagy: a dynamic relationship governed by nutrients and energy. Semin Cell Dev Biol 2014; 36: 121–129.CrossRefGoogle ScholarPubMed
Parkhitko, A, Myachina, F, Morrison, TA, et al., Tumorigenesis in tuberous sclerosis complex is autophagy and p62/sequestosome 1 (SQSTM1)-dependent. Proc Natl Acad Sci USA 2011; 108: 12455–12460.CrossRefGoogle ScholarPubMed
Wu, H, Che, X, Zheng, Q, et al., Caspases: a molecular switch node in the cross-talk between autophagy and apoptosis. Int J Biol Sci 2014; 10: 1072–1083.CrossRefGoogle Scholar
Marcelli, M, Shao, TC, Li, X, et al. Induction of apoptosis in BPH stromal cells by adenoviral-mediated overexpression of caspase-7 - PubMed. J Urol 2000; 164: 518–525.CrossRefGoogle Scholar
Wu, SS, Collins, MH, De Chadarevian, JP. Study of the regression process in cardiac rhabdomyomas. Pediatr Dev Pathol 2002; 5: 29–36.CrossRefGoogle ScholarPubMed
Lilienbaum, A, Relationship between the proteasomal system and autophagy – PubMed. Int J Biochem Mol Biol 2013; 4: 1–26.Google Scholar
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