Clinicopathological significance of mitochondrial D-Loop mutations in head and neck carcinoma

Abstract

Mitochondrial DNA mutations have been reported in several types of tumours, including head and neck squamous cell carcinoma (HNSCC). The noncoding region of the Displacement-Loop (D-Loop) has emerged as a mutational hotspot and we recently found that they were associated with prognosis and response to 5 fluorouracil (5FU) in colon cancers. In order to evaluate the frequence of D-Loop mutations in a large series of HNSCC and establish correlations with clinicopathologic parameters, we sequenced the D-Loop of 109 HNSCC before a treatment by neoadjuvant 5FU-cisplatin-based chemotherapy and surgery. Then, we correlated these mutations with prognosis and response to chemotherapy. A D-Loop mutation was identified in 21% of the tumors, the majority of them were located in a C-tract (D310). The prevalence of D310 mutations increased significantly with the number of cytosines in the matched normal tissue sequence (P ¼ 0.02). Hypopharyngeal cancer was significantly more frequent (P ¼ 0.03) and tobacco consumption more important (P ¼ 0.01) in the group of patients with D-Loop mutation. The presence of D-Loop mutation was not associated with prognosis or with response to neoadjuvant chemotherapy. These results suggest that D-Loop mutations should be considered as a cancer biomarker that may be useful for the early detection of HNSCC in individuals at risk of this cancer.

Mitochondrial DNA alterations correlate with the pathological status and the immunological ER, PR, HER-2/neu, p53 and Ki-67 expression in breast invasive ductal carcinoma

“…In addition to quantitative change of mtDNA copy number, several studies also evaluated the qualitative mtDNA D310 mutations in human types of cancers, including prostate (50,51), head and neck (52) and lung cancer (53,54), and esophageal squamous cell carcinoma (20), and some showed clinical significance. In breast cancer, a D-loop mutation, including D310 mutation, was identified as a poor prognostic factor (39).…”

Mitochondrial D-loop mutations can be detected in sporadic malignant tumours in dogs

“…Studies on mutations in the D-loop sequence were also conducted by Lièvre et al (21). Their analyses involved patients with head and neck tumours.…”

Mitochondrial DNA: The Alternative Molecular Marker for Cancer Detection and Treatment

“…Furthermore it is shown that the mutations previously reported within the ND2 gene in normal parotid tissue of smokers were not evident in these samples, but that a mutation hotspot occurs at nucleotide 4917 in oral SCC.It is concluded that the mtDNAmutations hotspot found in this study in particular nt186 are potential biomarkers for oral SCC. 20,26,27 D-loop mutations should be considered as a cancer biomarker that may be useful for the early detection of HNSCC in individuals at risk of this cancer. The presence of these mutations in saliva and serum of tobacco and alcohol consumers' should be investigated in further studies in order to evaluate their relevance in the screening of these cancers in association with other tumour specific molecular alterations.…”

“…The presence of these mutations in saliva and serum of tobacco and alcohol consumers' should be investigated in further studies in order to evaluate their relevance in the screening of these cancers in association with other tumour specific molecular alterations. 21,26 MtDNA as a marker in histopathologic grading in premalignant and malignant head and neck lesions Mitochondria are highly susceptible to oxidative damage and mitochondrial function decreases with oxidative damage, overall mitochondrial DNA content increases to compensate for general mitochondrial dysfunction. 9 Head and neck squamous cell carcinomas arise through premalignant intermediates and may be merely morphologic manifestations of accumulated genetic alterations.…”