Somatic mutations in plasma cell-free DNA are diagnostic markers for esophageal squamous cell carcinoma recurrence
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Masami Ueda1,2, Tomohiro Iguchi1, Takaaki Masuda1, Yujiro Nakahara2, Hidenari Hirata1, Ryutaro Uchi1, Atsushi Niida3, Kota Momose2, Shotaro Sakimura1, Kenichi Chiba3, Hidetoshi Eguchi1, Shuhei Ito1, Keishi Sugimachi1,4, Makoto Yamasaki2, Yutaka Suzuki5, Satoru Miyano3, Yuichiro Doki2, Masaki Mori2, Koshi Mimori1
1Department of Surgery, Kyushu University Beppu Hospital, Beppu 874-0838, Japan
2Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita 565-0871, Japan
3Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
4Department of Surgery, Fukuoka City Hospital, Fukuoka 812-0046, Japan
5Laboratory of Functional Genomics, Department of Medical Genome Sciences, Graduate School of Frontier Sciences, University of Tokyo, Kashiwa 277-8562, Japan
Koshi Mimori, email: [email protected]
Keywords: esophageal squamous cell carcinoma, cell-free DNA, next-generation sequencing, tumor recurrence, somatic mutation
Received: April 30, 2016 Accepted: July 28, 2016 Published: August 19, 2016
Objectives: 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.
Experimental Design: 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.
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