Clonal expansion of different mtDNA variants without selective advantage in solid tumors

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• Head and neck squamous cell carcinoma (HNSCC) is a significant global health concern.
• Mitochondrial DNA (mtDNA) mutations are frequently observed in various cancers, but their role in tumor development remains debated.
• The Warburg effect, a hallmark of cancer metabolism, is often linked to mtDNA alterations.

Purpose of the Study:

• To investigate tumor-specific mitochondrial DNA (mtDNA) mutations in head and neck squamous cell cancer.
• To determine the mechanism of mtDNA mutation accumulation in solid tumors.
• To assess whether mtDNA mutations are essential for the Warburg effect.

Main Methods:

• Analysis of mitochondrial DNA (mtDNA) heteroplasmy in blood and tumor tissues from patients with head and neck squamous cell cancer.
• Whole mtDNA sequencing (16.5 kb) to identify specific mutations and allele frequencies.
• Comparison of mtDNA genotypes between paired tumor and blood samples.

Main Results:

• Two individuals with head and neck squamous cell cancer exhibited mtDNA heteroplasmy in their blood.
• Tumor tissues in both cases were homoplasmic, containing only one of the two mtDNA alleles found in the blood.
• In one case, the tumor selected the wild-type allele, while in the other, it exclusively retained the mutant allele.
• The identified heteroplasmic sites in the D-loop region were the sole differences between tumor and blood mtDNA.

Conclusions:

• Tumor-specific mtDNA mutations in HNSCC appear to arise from clonal expansion of pre-existing alleles.
• The selection of specific mtDNA alleles (wild-type or mutant) in tumors suggests a random or stochastic process.
• mtDNA mutations are not a prerequisite for the metabolic alterations characteristic of cancer, such as the Warburg effect.