Pathogenic Heteroplasmic Somatic Mitochondrial DNA Mutation Confers Platinum-Resistance and Recurrence of High-Grade...

Area of Science:

• Oncology
• Genetics
• Biochemistry

Background:

• Platinum-based chemotherapy is a cornerstone treatment for ovarian cancer.
• Platinum resistance remains a significant challenge, limiting patient survival rates.
• The role of mitochondrial DNA (mtDNA) somatic mutations in platinum response is not fully understood.

Purpose of the Study:

• To investigate the association between mtDNA somatic mutations and platinum chemotherapy response in high-grade serous ovarian cancer (HGSOC).
• To explore the potential impact of these mutations on platinum resistance and disease relapse.

Main Methods:

• Next-generation sequencing (NGS) was utilized to identify mtDNA mutations in HGSOC patients.
• Germline and somatic mtDNA variants were analyzed.
• Tumor and paired non-tumor tissues were compared for metabolic profiles, specifically the lactate-to-pyruvate (L/P) ratio.

Main Results:

• 28 mtDNA somatic mutations were identified.
• Platinum-sensitive HGSOC patients showed more synonymous mutations, while platinum-resistant patients exhibited more missense mutations.
• Patients with heteroplasmic pathogenic mtDNA somatic mutations had a significantly higher prevalence of platinum resistance and relapse (80.0% vs. 16.7%, p=0.035).
• Tumor tissues displayed a higher L/P ratio compared to non-tumor tissues (p<0.001).
• Tumors with heteroplasmic pathogenic mtDNA mutations had a significantly higher L/P ratio (p=0.025).

Conclusions:

• Heteroplasmic pathogenic mtDNA somatic mutations may contribute to platinum resistance in ovarian cancer.
• These mutations might induce metabolic reprogramming, potentially by decreasing respiratory chain activity.
• The findings suggest a link between mtDNA mutations, altered cellular metabolism, and treatment failure in HGSOC.