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Clinical significance in oral cavity squamous cell carcinoma of pathogenic somatic mitochondrial mutations.

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.

SUBMITTER: Lai CH

PROVIDER: S-EPMC3683038 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Clinical significance in oral cavity squamous cell carcinoma of pathogenic somatic mitochondrial mutations.

Lai Chih-Hsiung CH Huang Shiang-Fu SF Liao Chun-Ta CT Chen I-How IH Wang Hung-Ming HM Hsieh Ling-Ling LL

PloS one 20130614 6

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 an ...[more]

PMID: 23799027

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Project description:BackgroundZinc-finger E-box binding homeobox 1 (ZEB-1), a member of the ZFH family, plays a key role in epithelial-mesenchymal transition during tumor progression in various cancers. However, little information is available on ZEB-1 expression in oral cavity squamous cell carcinoma (OSCC).MethodsThe expression levels of ZEB-1 and E-cadherin were assessed by immunohistochemistry in a cohort of 120 patients with OSCC treated by curative operation, and then the correlations between ZEB-1 and E-cadherin expression and clinical factors were evaluated, including patient prognosis. Quantitative real-time polymerase chain reaction (qRT-PCR) assays were performed to assess mRNA levels of ZEB-1 and E-cadherin in 20 matched OSCC specimens.ResultsPatients were followed up for a median period of 66 months (range 8-116 months), and 5-year overall survival was 68.3%. Positive ZEB-1 and E-cadherin immunostaining reactivity was detected in 64 (53.3%) and 53 (44.2%) patients, respectively. There was a negative correlation between ZEB-1 expression and E-cadherin expression. In addition, overexpression of ZEB-1 was significantly associated with recurrence, lymph node metastasis, and pathologic grading of patients, loss of E-cadherin was significantly associated with lymph node metastasis and pathologic grading of patients. Univariate analysis showed that increased ZEB-1 expression, loss of E-cadherin expression, lymph node metastasis, recurrence, and pathology grade were prognostic factors. In multivariate analysis, increased ZEB-1 expression and recurrence remained independent prognostic factors. In particular, patients with both ZEB-1 positivity and loss of E-cadherin expression had a poorer prognosis. qRT-PCR showed that ZEB-1 mRNA expression was higher in OSCC compared to the adjacent nontumorous tissues, while E-cadherin mRNA expression was lower in tumor tissues.ConclusionThis study shows that overexpression of ZEB-1 and loss of E-cadherin expression are significantly correlated with poor survival in OSCC patients, and ZEB-1 expression might serve as an independent prognostic biomarker of OSCC.

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Clinical significance in oral cavity squamous cell carcinoma of pathogenic somatic mitochondrial mutations.

Publications

Clinical significance in oral cavity squamous cell carcinoma of pathogenic somatic mitochondrial mutations.

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