title: Quantitative detection of circulating tumor-derived mitochondrial NADH subunit variants as a potential prognostic biomarker for oral cancer.
abstract: Circulating tumor cells (CTCs) and/or their relating molecules are promising determinants during the course of cancer treatment, especially for post-therapeutic monitoring. We recently reported the clinical relevance of detecting circulating tumor-associated mutant mitochondrial DNAs (mut-mtDNAs) at three different regions including the displacement loop, 12S-rRNA and 16S-rRNA in oral squamous cell carcinomas (OSCCs). In the present study, to further investigate if the other mut-mtDNAs have novel efficiency for detecting potential tumoral micrometastasis, mut-mtDNAs on the ND2 and ND3 regions of the genome in 240 clinical samples from patients with OSCC were assessed in vitro and in vivo by quantitative real-time PCR combined with high-resolution melting curve analysis. Furthermore, the clinical relevance was evaluated by the area under the receiver operating characteristic curve (AUC) analysis. Three discrete sequence variations were identified in OSCC derived cell lines at the regions of ND2 (T:A to C:G at position 5108) and ND3 (A:T to G:C at position 10397 and C:G to T:A at position 10400), whereas no mutation was observed in normal control human normal oral keratinocytes. In OSCC patients examined, the presence of mut-mtDNAs in serum during the postoperative period accurately predicted poor prognoses (ND2 AUC, 0.761; ND3 AUC, 0.704). The data presented here provide a novel approach for detecting the circulating mut-mtDNAs that are promising molecular markers for evaluating tumoral micrometastasis in OSCCs.
authors.affiliation: Department of Oral Science, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba 260‑8670, Japan.
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Uzawa
authors.affiliation: Department of Dentistry and Oral-Maxillofacial Surgery, Chiba University Hospital, Chiba University, Chuo-ku, Chiba 260‑8670, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kasamatsu
authors.affiliation: Department of Oral Science, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba 260‑8670, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Baba
authors.affiliation: Department of Oral Science, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba 260‑8670, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kimura
authors.affiliation: Department of Dentistry and Oral-Maxillofacial Surgery, Chiba University Hospital, Chiba University, Chuo-ku, Chiba 260‑8670, Japan.
authors.forename: Dai
authors.initials: D
authors.lastname: Nakashima
authors.affiliation: Department of Dentistry and Oral-Maxillofacial Surgery, Chiba University Hospital, Chiba University, Chuo-ku, Chiba 260‑8670, Japan.
authors.forename: Morihiro
authors.initials: M
authors.lastname: Higo
authors.affiliation: Department of Dentistry and Oral-Maxillofacial Surgery, Chiba University Hospital, Chiba University, Chuo-ku, Chiba 260‑8670, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Sakamoto
authors.affiliation: Department of Dentistry and Oral-Maxillofacial Surgery, Chiba University Hospital, Chiba University, Chuo-ku, Chiba 260‑8670, Japan.
authors.forename: Katsunori
authors.initials: K
authors.lastname: Ogawara
authors.affiliation: Department of Medical Oncology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba 260‑8670, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Shiiba
authors.affiliation: Department of Oral Science, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba 260‑8670, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Tanzawa
mesh_terms: D000818:Animals; D019540:Area Under Curve; D014408:Biomarkers, Tumor / Q000097:blood / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D004272:DNA, Mitochondrial / Q000097:blood / Q000235:genetics; D042967:Electron Transport Complex I / Q000097:blood / Q000235:genetics*; D006801:Humans; D051379:Mice; D009062:Mouth Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D009154:Mutation; D009245:NADH Dehydrogenase / Q000097:blood / Q000235:genetics*; D009368:Neoplasm Transplantation; D009360:Neoplastic Cells, Circulating / Q000378:metabolism*; D011379:Prognosis
chemical_list: D014408:Biomarkers, Tumor; D004272:DNA, Mitochondrial; D009245:NADH Dehydrogenase; C521326:NADH dehydrogenase subunit 2, human; D042967:Electron Transport Complex I; C114961:MT-ND3 protein, human