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Acute cardiac dysfunction in patients with ovarian cancer treated with Niraparib due to TFAM mutation: A case series
1Department of Gynecology and Obstetrics, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, PR China.
Background:
Ovarian cancer is a leading cause of gynecological cancer mortality. Despite Niraparib's efficacy in increasing progression-free survival for recurrent ovarian cancer, its potential cardiotoxic effects are underexplored.
Objective:
We performed a case series analysis involving two postmenopausal sisters who developed heart failure subsequent to Niraparib therapy for recurrent ovarian cancer.
Methods:
Utilizing targeted next-generation sequencing (NGS), we identified a novel missense mutation c.98T>A in Mitochondrial Transcription Factor A (TFAM) gene, which was subsequently confirmed by Sanger sequencing. To investigate the cardiotoxic effects of Niraparib, we generated human induced pluripotent stem cell-derived cardiomyocytes (hiPSCCMs) carrying the identified mutation. The impact of the mutation on gene expression and protein levels was evaluated through real-time PCR and Western blot analyses.
Results:
Two postmenopausal sisters treated with Niraparib suffered significant cardiac dysfunction. NGS identified a novel c.98T>A variant in TFAM gene, resulting in a missense mutation. HEK293T cells transfected with mutant plasmids demonstrated normal expression of full-length TFAM mRNA and protein. hiPSCCMs model revealed the variant alone did not induce cardiomyopathy. However, it predisposed to Niraparib-induced cardiomyopathy-like toxicity, mediated by metabolic dysregulation and increased cellular apoptosis CONCLUSION: Our study revealed a novel TFAM variant which might induce potential cardiovascular toxicity of anticancer Niraparib therapies.
Insights
A novel mitochondrial transcription factor A (TFAM) gene variant may increase cardiovascular toxicity risk in ovarian cancer patients undergoing Niraparib treatment, leading to heart failure. This TFAM mutation predisposes cells to Niraparib-induced cardiotoxicity.
Area of Science:
- Oncology
- Genetics
- Cardiology
Background:
- Ovarian cancer is a major cause of gynecological cancer mortality.
- Niraparib improves progression-free survival in recurrent ovarian cancer but its cardiotoxicity is not well understood.
Purpose of the Study:
- To investigate the potential cardiotoxic effects of Niraparib in patients with a specific genetic mutation.
- To analyze a case series of two sisters who developed heart failure after Niraparib therapy for ovarian cancer.
Main Methods:
- Targeted next-generation sequencing (NGS) and Sanger sequencing identified a novel missense mutation (c.98T>A) in the Mitochondrial Transcription Factor A (TFAM) gene.
- Human induced pluripotent stem cell-derived cardiomyocytes (hiPSCCMs) with the TFAM mutation were generated to model Niraparib's cardiotoxic effects.
- Real-time PCR and Western blot analyzed gene expression and protein levels.
Main Results:
- Two postmenopausal sisters experienced significant cardiac dysfunction while on Niraparib therapy.
- A novel TFAM gene variant (c.98T>A) was identified.
- The TFAM variant alone did not cause cardiomyopathy but predisposed hiPSCCMs to Niraparib-induced toxicity, involving metabolic dysregulation and apoptosis.
Conclusions:
- A novel TFAM variant may contribute to the cardiovascular toxicity of Niraparib in ovarian cancer treatment.
- This finding highlights the importance of genetic factors in predicting and understanding anticancer drug cardiotoxicity.
