Association of Pathogenic Missense and Nonsense Mutations in Mitochondrial COII Gene with Familial Adenomatous Polyposis (FAP)

Nuclear genetic mutations have been extensively investigated in solid tumors. However, the role of the mitochondrial genome remains uncertain. Since the metabolism of solid tumors is associated with aerobic glycolysis and high lactate production, tumors may have mitochondrial dysfunctions. Familial adenomatous polyposis (FAP) is a rare form‌ of colorectal cancer and an autosomal dominant inherited condition that is characterized by the progress of numerous adenomatous polyps in the rectum and colon. The present study aimed at understanding the nature and effect of mitochondrial cytochrome c oxidase subunit 2 (COII) gene mutations in FAP tumorigenesis. Fifty-six (26 familial and 30 sporadic) FAP patients and 60 normal controls were enrolled in this study. COII point mutations were evaluated by PCR and direct sequencing methods, and a total of 7 mtDNA mutations were detected (3 missense, 1 nonsense, and 3 synonymous variations). Novel non-synonymous COII gene mutations were mostly in heteroplasmic state. These mutations change amino acid residues in the N-terminal and C-terminal regions of COXII. Bioinformatics analysis and three-dimensional structural modeling predicted that these missense and nonsense mutations have functional importance, and mainly affected on cytochrome c oxidase (complex IV). Also, FAP patients carried a meaningfully higher prevalence of mutations in the COII gene in comparison with healthy controls (P < 0.001). Analysis of cancer-associated mtDNA mutation could be an invaluable tool for molecular assessment of FAP so that these findings can be helpful for the development of potential new biomarkers in the diagnosis of cancer for future clinical assessments.