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タイトル: Circulating cell-free DNA-based epigenetic assay can detect early breast cancer
著者: Uehiro, Natsue
Sato, Fumiaki
Pu, Fengling
Tanaka, Sunao
Kawashima, Masahiro  kyouindb  KAKEN_id  orcid https://orcid.org/0000-0002-4738-8351 (unconfirmed)
Kawaguchi, Kosuke  kyouindb  KAKEN_id  orcid https://orcid.org/0000-0002-3161-7981 (unconfirmed)
Sugimoto, Masahiro
Saji, Shigehira
Toi, Masakazu  KAKEN_id  orcid https://orcid.org/0000-0003-1488-9958 (unconfirmed)
著者名の別形: 佐藤, 史顕
川島, 雅央
戸井, 雅和
キーワード: Breast cancer
Circulating DNA
DNA methylation
Early detection
Epigenetics
発行日: 19-Dec-2016
出版者: BioMed Central Ltd.
誌名: Breast Cancer Research
巻: 18
号: 1
論文番号: 129
抄録: Background: Circulating cell-free DNA (cfDNA) has recently been recognized as a resource for biomarkers of cancer progression, treatment response, and drug resistance. However, few have demonstrated the usefulness of cfDNA for early detection of cancer. Although aberrant DNA methylation in cfDNA has been reported for more than a decade, its diagnostic accuracy remains unsatisfactory for cancer screening. Thus, the aim of the present study was to develop a highly sensitive cfDNA-based system for detection of primary breast cancer (BC) using epigenetic biomarkers and digital PCR technology. Methods: Array-based genome-wide DNA methylation analysis was performed using 56 microdissected breast tissue specimens, 34 cell lines, and 29 blood samples from healthy volunteers (HVs). Epigenetic markers for BC detection were selected, and a droplet digital methylation-specific PCR (ddMSP) panel with the selected markers was established. The detection model was constructed by support vector machine and evaluated using cfDNA samples. Results: The methylation array analysis identified 12 novel epigenetic markers (JAK3, RASGRF1, CPXM1, SHF, DNM3, CAV2, HOXA10, B3GNT5, ST3GAL6, DACH1, P2RX3, and chr8:23572595) for detecting BC. We also selected four internal control markers (CREM, GLYATL3, ELMOD3, and KLF9) that were identified as infrequently altered genes using a public database. A ddMSP panel using these 16 markers was developed and detection models were constructed with a training dataset containing cfDNA samples from 80 HVs and 87 cancer patients. The best detection model adopted four methylation markers (RASGRF1, CPXM1, HOXA10, and DACH1) and two parameters (cfDNA concentration and the mean of 12 methylation markers), and, and was validated in an independent dataset of 53 HVs and 58 BC patients. The area under the receiver operating characteristic curve for cancer-normal discrimination was 0.916 and 0.876 in the training and validation dataset, respectively. The sensitivity and the specificity of the model was 0.862 (stages 0-I 0.846, IIA 0.862, IIB-III 0.818, metastatic BC 0.935) and 0.827, respectively. Conclusion: Our epigenetic-marker-based system distinguished BC patients from HVs with high accuracy. As detection of early BC using this system was comparable with that of mammography screening, this system would be beneficial as an optional method of screening for BC.
著作権等: © The Author(s). 2016 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
URI: http://hdl.handle.net/2433/218380
DOI(出版社版): 10.1186/s13058-016-0788-z
PubMed ID: 27993161
出現コレクション:学術雑誌掲載論文等

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