Mitochondrial DNA mutations in head and neck squamous cell carcinoma: a systematic review and meta-analysis

Head and neck squamous cell carcinoma (HNSCC) cause approximately 95% of head and neck malignancies. Clinicopathological predictions are limited, and mitochondrial DNA (mtDNA) mutations have emerged as possible biomarkers. This systematic review and meta-analysis aimed to quantify the relative contributions of several mitochondrial genome regions to the overall mutational burden in HNSCC, thereby contextualizing their potential biological importance.

A systematic review and meta-analysis were conducted in accordance with the PRISMA criteria. PubMed, EMBASE, Scopus, and Web of Science were searched up to May 2025. Eligible studies reporting somatic mtDNA mutations in HNSCC were included. The quality of included studies was assessed using the Joanna Briggs Institute (JBI) critical appraisal tools. Proportional meta-analyses under random-effects models determined pooled mutation shares for six mtDNA regions.

Seventeen studies were included. The D-loop was the major hotspot (67%, 95% CI: 0.28-0.91; I² = 93.2%). ND mutations represented 29% (95% CI: 0.20-0.40), predominantly in ND1, ND2, ND4, ND5, and ND4L. COX (12%), rRNA (13%), and tRNA (9%) mutations contributed variably, while CYTB mutations were less frequent but constant (8%, I² = 0%). Considerable heterogeneity was seen in most regions.

The D-loop and ND genes dominate the mutational spectrum of HNSCC. While these findings highlight recurrent alternations in mtDNA, further studies are required to evaluate their potential as a biomarker for diagnosis and prognosis.