Abstract
Somatic mutations affecting the mitochondrial DNA (mtDNA) have been frequently observed in human cancers and proposed as important oncological biomarkers. However, the clinical significance of mtDNA mutations in cancer remains unclear. This study was therefore performed to explore the possible clinical use in assessing oral squamous cell carcinoma (OSCC) of pathogenic mtDNA mutations. The entire mitochondrial genome of 300 OSCC with their matched control DNAs was screened by direct sequencing and criteria were set to define a pathogenic somatic mutation. The patients' TP53 R72P genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism. The relationships between pathogenic somatic mutations, clinicopathogical features, TP53 R72P genotype and clinical prognosis were analyzed. Overall, 645 somatic mtDNA mutations were identified and 91 of these mutations were defined as pathogenic. About one quarter (74/300) of the OSCC tumor samples contained pathogenic mutations. Individuals with the TP53 R allele had a higher frequency of pathogenic somatic mutation than those with the PP genotype. Kaplan-Meier analysis indicated that TP53 R allele patients with pathogenic somatic mutations demonstrated a significant association with a poorer disease-free survival than other individuals (HR = 1.71; 95% CI, 1.15–2.57; p = 0.009) and this phenomenon still existed after adjusting for mtDNA haplogroup, tumor stage with treatment regimens, differentiation and age at diagnosis (HR = 1.59; 95% CI, 1.06–2.40; p = 0.03). Subgroup analyses showed that this phenomenon was limited to patients who received adjuvant radiotherapy/chemo-radiotherapy after surgery. The results strongly indicated that pathogenic mtDNA mutations are a potential prognostic marker for OSCCs. Furthermore, functional mitochondria may play an active role in cancer development and the patient's response to radiotherapy/chemo-radiotherapy.
Highlights
Oral cancer is currently a major global health issue
Our results suggest for the first time that pathogenic mitochondrial DNA (mtDNA) mutations are potential prognostic markers for oral squamous cell carcinoma (OSCC) and TP53 R72P polymorphism was associated with pathogenic mtDNA mutations
The most frequent mutations were in the D310 polycytidine stretch region (C-tract, 12–18 cytidine bases interrupted by a thymidine base at position 310), which is where 165 (25.6%, 165/645) mutations were found (Figure 1A)
Summary
Oral cancer is currently a major global health issue. In Taiwan, oral cancer has been the fourth most common cancer in men since 2006 [1]. Observations in human cancers and animal models have provided concrete evidence indicating that tumor development proceeds via a succession of cellular DNA alterations, each conferring a growth advantage and that these changes lead to the progressive conversion of normal cells into cancer cells [4]. MtDNA has a higher mutation rate than nuclear DNA [7,8] and mutations are commonly found in different types of human tumors including head and neck cancers [9,10]. These findings suggest a potential role for mtDNA mutations in tumor development. The clinical use of these mtDNA mutations was not addressed
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