Circulating tumor-derived mutant mitochondrial DNA: a predictive biomarker of clinical prognosis in human squamous cell carcinoma.
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Katsuhiro Uzawa1,2, Takao Baba1, Fumihiko Uchida3, Masanobu Yamatoji3, Atsushi Kasamatsu1,2, Yosuke Sakamoto2, Katsunori Ogawara2, Masashi Shiiba1,2, Hiroki Bukawa3, Hideki Tanzawa1,2
1 Department of Clinical Molecular Biology, Graduate School of Medicine, Chiba University, Chiba, Japan
2 Department of Dentistry-Oral and Maxillofacial Surgery, Chiba University Hospital, Chiba, Japan
3 Department of Oral and Maxillofacial Surgery, Clinical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki, Japan
Katsuhiro Uzawa, email:
Keywords: squamous cell carcinoma, mitochondrial DNA; high-resolution melting curve analysis; circulating tumor-derived DNA; prognosis
Received: June 14, 2012, Accepted: July 23, 2012, Published: July 25, 2012
While circulating tumor-derived molecules have been identified in a variety of malignant tumors, it is sometimes difficult to detect the molecular targets due to the lower serum concentration. We report that evaluation of circulating tumor-derived mitochondrial DNA (mtDNA) seems to have novel efficiency for detecting tumoral micrometastasis. In murine xenografting human oral cancer cells, human mtDNAs could be quantitatively detected from multiple organs and blood samples whereas human nucleic DNAs could not. We also determined if this mtDNA blood test was relevant for patients with oral cancer with no histologic evidence of tumoral cells in their surgical margins. For this, mtDNA from normal and tumorous tissues and serum mtDNA obtained pre and postoperatively was examined at three different regions including the displacement loop, 12S-rRNA, and 16S-rRNA. All recurring patients had significantly higher amounts of mutant mtDNAs in the tumoral tissues compared with the non-recurring group. More importantly, on the blood test with the cut-off point by receiver operating characteristic (ROC) curve analysis, while the vast majority of serum mtDNA samples obtained postoperatively in the recurring cases maintained significantly higher amounts of mutant mtDNAs, the non-recurring cases did not, and they showed good prognosis. This is the first report of this approach for managing patients after resection of oral tumors, and may have substantial diagnostic potential for other tumoral types.
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