title: Somatic mutations in plasma cell-free DNA are diagnostic markers for esophageal squamous cell carcinoma recurrence.
abstract: OBJECTIVE
  Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive malignancies owing to the high frequency of tumor recurrence. The identification of markers for early ESCC diagnosis and prediction of recurrence is expected to improve the long-term prognosis. Therefore, we searched for associations between tumor recurrence and cell-free DNA (cfDNA) mutations in blood plasma, which contains genetic markers for various cancer types.
  
  
  METHODS
  Genomic DNA from tumors and cfDNA from plasma were obtained from 13 patients undergoing treatment for newly diagnosed ESCC. Next-generation sequencing of cfDNA in plasma was performed to identify mutations in 53 cancer-related genes, in which recurrent mutations were previously detected in ESCC. cfDNA mutational profiles were compared before and after tumor resection in four patients. Furthermore, somatic mutations in serial plasma samples were monitored after treatment in four patients.
  
  
  RESULTS
  We identified multiple concordant somatic mutations in cfDNA and primary tumor samples from 10 patients (83.3%) and in cfDNA and metastatic tumor samples from one patient (100%). Furthermore, the allele frequency of the concordant mutations in cfDNA changed concomitantly with tumor burden and increased approximately 6 months earlier than the detection of tumor recurrences by imaging tests in two patients. Conventional biomarkers, such as SCC and p53-Ab, did not reflect tumor recurrences.
  
  
  CONCLUSIONS
  The present multigene panel, which enabled the diagnosis of tumor recurrence with greater accuracy than did using standard tumor markers or imaging methods, is expected to greatly facilitate standard, postoperative follow-up monitoring in ESCC.
authors.affiliation: Department of Surgery, Kyushu University Beppu Hospital, Beppu 874-0838, Japan.|Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita 565-0871, Japan.
authors.forename: Masami
authors.initials: M
authors.lastname: Ueda
authors.affiliation: Department of Surgery, Kyushu University Beppu Hospital, Beppu 874-0838, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Iguchi
authors.affiliation: Department of Surgery, Kyushu University Beppu Hospital, Beppu 874-0838, Japan.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Masuda
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita 565-0871, Japan.
authors.forename: Yujiro
authors.initials: Y
authors.lastname: Nakahara
authors.affiliation: Department of Surgery, Kyushu University Beppu Hospital, Beppu 874-0838, Japan.
authors.forename: Hidenari
authors.initials: H
authors.lastname: Hirata
authors.affiliation: Department of Surgery, Kyushu University Beppu Hospital, Beppu 874-0838, Japan.
authors.forename: Ryutaro
authors.initials: R
authors.lastname: Uchi
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Niida
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita 565-0871, Japan.
authors.forename: Kota
authors.initials: K
authors.lastname: Momose
authors.affiliation: Department of Surgery, Kyushu University Beppu Hospital, Beppu 874-0838, Japan.
authors.forename: Shotaro
authors.initials: S
authors.lastname: Sakimura
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Chiba
authors.affiliation: Department of Surgery, Kyushu University Beppu Hospital, Beppu 874-0838, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Eguchi
authors.affiliation: Department of Surgery, Kyushu University Beppu Hospital, Beppu 874-0838, Japan.
authors.forename: Shuhei
authors.initials: S
authors.lastname: Ito
authors.affiliation: Department of Surgery, Kyushu University Beppu Hospital, Beppu 874-0838, Japan.|Department of Surgery, Fukuoka City Hospital, Fukuoka 812-0046, Japan.
authors.forename: Keishi
authors.initials: K
authors.lastname: Sugimachi
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita 565-0871, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Yamasaki
authors.affiliation: Laboratory of Functional Genomics, Department of Medical Genome Sciences, Graduate School of Frontier Sciences, University of Tokyo, Kashiwa 277-8562, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Miyano
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita 565-0871, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Doki
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita 565-0871, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Mori
authors.affiliation: Department of Surgery, Kyushu University Beppu Hospital, Beppu 874-0838, Japan.
authors.forename: Koshi
authors.initials: K
authors.lastname: Mimori
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000097:blood*; D002294:Carcinoma, Squamous Cell / Q000097:blood / Q000175:diagnosis* / Q000235:genetics / Q000601:surgery; D000074141:Circulating Tumor DNA / Q000235:genetics*; D004252:DNA Mutational Analysis / Q000379:methods; D004938:Esophageal Neoplasms / Q000097:blood / Q000175:diagnosis* / Q000235:genetics / Q000601:surgery; D000077277:Esophageal Squamous Cell Carcinoma; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009364:Neoplasm Recurrence, Local / Q000097:blood / Q000175:diagnosis* / Q000235:genetics; D011379:Prognosis; D011446:Prospective Studies; D014057:Tomography, X-Ray Computed; D047368:Tumor Burden / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D000074141:Circulating Tumor DNA
keywords: cell-free DNA; esophageal squamous cell carcinoma; next-generation sequencing; somatic mutation; tumor recurrence