Pathogenic Heteroplasmic Somatic Mitochondrial DNA Mutation Confers Platinum-Resistance and Recurrence of High-Grade Serous Ovarian Cancer

Abstract

Jing Ni,1,2 Yan Wang,3 Xianzhong Cheng,1 Fang Teng,4 Congyang Wang,3 Suping Han,2 Xiaoxiang Chen,1 Wenwen Guo3 1Department of Gynecologic Oncology, The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing, 210009, People’s Republic of China; 2Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, People’s Republic of China; 3Department of Pathology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, People’s Republic of China; 4Department of Gynecology, Women’s Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), Nanjing 210004, People’s Republic of ChinaCorrespondence: Wenwen GuoDepartment of Pathology, The Second Affiliated Hospital of Nanjing Medical University, 121# Jiangjiayuan Road, Nanjing, Jiangsu 210011, People’s Republic of ChinaTel [phone]Email [email protected] HanDepartment of Gynecology, The First Affiliated Hospital of Nanjing Medical University, 300# Guangzhou Road, Nanjing, Jiangsu 210009, People’s Republic of ChinaTel [phone]Email [email protected]: Platinum resistance is a primary barrier to improving the survival rate of ovarian cancer. The relationship between mtDNA somatic mutations and response to platinum-based chemotherapy in ovarian cancer has not been well clarified.Patients and Methods: Here, we employed the next-generation sequencing (NGS) platform to identify mtDNA mutations of the unrelated high-grade serous ovarian cancer (HGSOC) patients.Results: We identified 569 germline variants and 28 mtDNA somatic mutations, and found the platinum-sensitive relapsed HGSOC patients had more synonymous mutations while the platinum-resistant relapsed HGSOC patients had more missense mutations in the mtDNA somatic mutations. Meanwhile, we found that the HGSOC patients who harbored heteroplasmic pathogenic mtDNA somatic mutations had significantly higher prevalence of both platinum-resistance and relapse than those without (80.0% versus 16.7%, p=0.035). Additionally, we observed that the tumor tissues had significantly higher lactate-to-pyruvate (L/P) ratio than the paired nontumor tissues (p< 0.001), and L/P ratio of tumors with any heteroplasmic pathogenic mtDNA mutations was significantly higher than that of the tumors free of pathogenic mtDNA mutations (p=0.025).Conclusion: Our findings indicate that these heteroplasmic pathogenic mtDNA somatic mutations may cause decreased respiratory chain activity and lead to the metabolism remodeling that seem to be beneficial for progression of both platinum-based chemotherapy resistance and relapse.Keywords: high-grade serous ovarian cancer, chemotherapy, heteroplasmy, mitochondrial DNA mutation

Keywords

• high-grade serous ovarian cancer
• chemotherapy
• heteroplasmy
• mitochondrial dna mutation