{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T06:24:25Z","timestamp":1790144665169,"version":"4.0.1"},"reference-count":34,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,7,18]],"date-time":"2019-07-18T00:00:00Z","timestamp":1563408000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2019,7,18]],"date-time":"2019-07-18T00:00:00Z","timestamp":1563408000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001691","name":"MEXT | Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP18K16776"],"award-info":[{"award-number":["JP18K16776"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Liquid biopsies of circulating tumor DNA (ctDNA) have recently been used as a non-invasive diagnostic tool for detecting tumor-specific mutations. We present a study of ctDNA liquid biopsies in gynecological cancer using an ultrasensitive next-generation sequencing-based method for ctDNA detection named CAncer Personalized Profiling by deep Sequencing (CAPP-Seq). We performed CAPP-Seq with plasma-ctDNA obtained from 16 patients with gynecological cancer. In all cases, at least one non-synonymous somatic mutation was detected in the ctDNA. In the pre-treatment ctDNA, 4 of 16, 4\/16, 5\/16, 2\/16, 2\/16, and 2\/16 patients had <jats:italic>TP53<\/jats:italic>, <jats:italic>KRAS<\/jats:italic>, <jats:italic>APC<\/jats:italic>, <jats:italic>PIK3CA<\/jats:italic>, <jats:italic>BRCA1<\/jats:italic>, and <jats:italic>EGFR<\/jats:italic> mutations, respectively. <jats:italic>MET<\/jats:italic> gene copy-number gains were detected in the ctDNA of 2 of 16 patients, and FISH analysis of the paired tumor samples confirmed these results. In 2 neoadjuvant chemotherapy-treated ovarian cancer patients, the changes in gene mutation patterns were associated with the treatment response. These findings suggest that CAPP-Seq-based liquid biopsies can be used for the genetic characterization of independent gynecological cancers with high frequency, and might be clinically useful for non-invasive tumor genotyping and therapeutic response monitoring.<\/jats:p>","DOI":"10.1038\/s41598-019-47030-w","type":"journal-article","created":{"date-parts":[[2019,7,18]],"date-time":"2019-07-18T10:02:38Z","timestamp":1563444158000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Liquid biopsy-based comprehensive gene mutation profiling for gynecological cancer using CAncer Personalized Profiling by deep Sequencing"],"prefix":"10.1038","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6422-325X","authenticated-orcid":false,"given":"Naoyuki","family":"Iwahashi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuko","family":"Sakai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoko","family":"Noguchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamaki","family":"Yahata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hitomi","family":"Matsukawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saori","family":"Toujima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuto","family":"Nishio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuhiko","family":"Ino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,7,18]]},"reference":[{"key":"47030_CR1","doi-asserted-by":"publisher","first-page":"244","DOI":"10.1002\/path.4278","volume":"232","author":"BG Blair","year":"2014","unstructured":"Blair, B. G., Bardelli, A. & Park, B. H. Somatic alterations as the basis for resistance to targeted therapies. J Pathol 232, 244\u2013254 (2014).","journal-title":"J Pathol"},{"key":"47030_CR2","doi-asserted-by":"publisher","first-page":"426","DOI":"10.1038\/nrc3066","volume":"11","author":"H Schwarzenbach","year":"2011","unstructured":"Schwarzenbach, H., Hoon, D. S. & Pantel, K. Cell-free nucleic acids as biomarkers in cancer patients. Nat Rev Cancer 11, 426\u2013437 (2011).","journal-title":"Nat Rev Cancer"},{"key":"47030_CR3","doi-asserted-by":"publisher","first-page":"340","DOI":"10.1056\/NEJMra0907178","volume":"364","author":"U McDermott","year":"2011","unstructured":"McDermott, U., Downing, J. R. & Stratton, M. R. Genomics and the continuum of cancer care. N Engl J Med 364, 340\u2013350 (2011).","journal-title":"N Engl J Med"},{"key":"47030_CR4","doi-asserted-by":"publisher","first-page":"532","DOI":"10.1038\/nature11156","volume":"486","author":"S Misale","year":"2012","unstructured":"Misale, S. et al. Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature 486, 532\u2013536 (2012).","journal-title":"Nature"},{"key":"47030_CR5","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1038\/nature12065","volume":"497","author":"M Murtaza","year":"2013","unstructured":"Murtaza, M. et al. Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature 497, 108\u2013112 (2013).","journal-title":"Nature"},{"key":"47030_CR6","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1016\/S0009-8981(01)00665-9","volume":"313","author":"M Stroun","year":"2001","unstructured":"Stroun, M., Lyautey, J., Lederrey, C., Olson-Sand, A. & Anker, P. About the possible origin and mechanism of circulating DNA apoptosis and active DNA release. Clin Chim Acta 313, 139\u2013142 (2001).","journal-title":"Clin Chim Acta"},{"key":"47030_CR7","doi-asserted-by":"publisher","first-page":"983","DOI":"10.1007\/s13277-012-0634-6","volume":"34","author":"PO Delgado","year":"2013","unstructured":"Delgado, P. O. et al. Characterization of cell-free circulating DNA in plasma in patients with prostate cancer. Tumour Biol 34, 983\u2013986 (2013).","journal-title":"Tumour Biol"},{"key":"47030_CR8","doi-asserted-by":"publisher","first-page":"1902","DOI":"10.1158\/1078-0432.CCR-12-1913","volume":"19","author":"M Peeters","year":"2013","unstructured":"Peeters, M. et al. Massively parallel tumor multigene sequencing to evaluate response to panitumumab in a randomized phase III study of metastatic colorectal cancer. Clin Cancer Res 19, 1902\u20131912 (2013).","journal-title":"Clin Cancer Res"},{"key":"47030_CR9","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1158\/1055-9965.EPI-14-0895","volume":"24","author":"M Qiu","year":"2015","unstructured":"Qiu, M. et al. Circulating tumor DNA is effective for the detection of EGFR mutation in non-small cell lung cancer: a meta-analysis. Cancer Epidemiol Biomarkers Prev 24, 206\u2013212 (2015).","journal-title":"Cancer Epidemiol Biomarkers Prev"},{"key":"47030_CR10","doi-asserted-by":"publisher","first-page":"3375","DOI":"10.1200\/JCO.2016.66.7162","volume":"34","author":"GR Oxnard","year":"2016","unstructured":"Oxnard, G. R. et al. Association Between Plasma Genotyping and Outcomes of Treatment With Osimertinib (AZD9291) in Advanced Non-Small-Cell Lung Cancer. J Clin Oncol 34, 3375\u20133382 (2016).","journal-title":"J Clin Oncol"},{"key":"47030_CR11","doi-asserted-by":"publisher","first-page":"302","DOI":"10.1126\/scitranslmed.aab0021","volume":"7","author":"I Garcia-Murillas","year":"2015","unstructured":"Garcia-Murillas, I. et al. Mutation tracking in circulating tumor DNA predicts relapse in early breast cancer. Sci Transl Med 7, 302\u2013133 (2015).","journal-title":"Sci Transl Med"},{"key":"47030_CR12","doi-asserted-by":"crossref","unstructured":"Cancer Genome Arlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature 474, 609\u2013615 (2011).","DOI":"10.1038\/nature10166"},{"key":"47030_CR13","doi-asserted-by":"crossref","unstructured":"Cancer Genome Arlas Research Network.\u00a0Integrated genomic characterization of endometrial carcinoma. Nature 497, 67\u201373 (2013).","DOI":"10.1038\/nature12113"},{"key":"47030_CR14","doi-asserted-by":"crossref","unstructured":"Cancer Genome Arlas Research Network.\u00a0Integrated genomic and molecular characterization of cervical cancer. Nature 543, 378\u2013384 (2017).","DOI":"10.1038\/nature21386"},{"key":"47030_CR15","doi-asserted-by":"publisher","first-page":"548","DOI":"10.1038\/nm.3519","volume":"20","author":"AM Newman","year":"2014","unstructured":"Newman, A. M. et al. An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage. Nat Med 20, 548\u2013554 (2014).","journal-title":"Nat Med"},{"key":"47030_CR16","doi-asserted-by":"publisher","first-page":"547","DOI":"10.1038\/nbt.3520","volume":"34","author":"AM Newman","year":"2016","unstructured":"Newman, A. M. et al. Integrated digital error suppression for improved detection of circulating tumor DNA. Nat Biotechnol 34, 547\u2013555 (2016).","journal-title":"Nat Biotechnol"},{"key":"47030_CR17","doi-asserted-by":"publisher","first-page":"364","DOI":"10.1126\/scitranslmed.aai8545","volume":"8","author":"F Scherer","year":"2016","unstructured":"Scherer, F. et al. Distinct biological subtypes and patterns of genome evolution in lymphoma revealed by circulating tumor DNA. Sci Transl Med 8, 364\u2013155 (2016).","journal-title":"Sci Transl Med"},{"key":"47030_CR18","doi-asserted-by":"publisher","first-page":"2688","DOI":"10.1158\/1078-0432.CCR-17-3704","volume":"24","author":"J Przybyl","year":"2018","unstructured":"Przybyl, J. et al. Combination Approach for Detecting Different Types of Alterations in Circulating Tumor DNA in Leiomyosarcoma. Clin Cancer Res 24, 2688\u20132699 (2018).","journal-title":"Clin Cancer Res"},{"key":"47030_CR19","doi-asserted-by":"publisher","first-page":"eaan2415","DOI":"10.1126\/scitranslmed.aan2415","volume":"9","author":"J Phallen","year":"2017","unstructured":"Phallen, J. et al. Direct detection of early-stage cancers using circulating tumor DNA. Sci Transl Med 9, eaan2415 (2017).","journal-title":"Sci Transl Med"},{"key":"47030_CR20","doi-asserted-by":"publisher","first-page":"926","DOI":"10.1126\/science.aar3247","volume":"359","author":"JD Cohen","year":"2018","unstructured":"Cohen, J. D. et al. Detection and localization of surgically resectable cancers with a multi-analyte blood test. Science 359, 926\u2013930 (2018).","journal-title":"Science"},{"key":"47030_CR21","doi-asserted-by":"publisher","first-page":"813","DOI":"10.1158\/1541-7786.MCR-17-0594","volume":"16","author":"RC Arend","year":"2018","unstructured":"Arend, R. C. et al. Molecular Response to Neoadjuvant Chemotherapy in High-Grade Serous Ovarian Carcinoma. Mol Cancer Res 16, 813\u2013824 (2018).","journal-title":"Mol Cancer Res"},{"key":"47030_CR22","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms11815","volume":"7","author":"JJ Chabon","year":"2016","unstructured":"Chabon, J. J. et al. Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients. Nat Commun 7, 11815 (2016).","journal-title":"Nat Commun"},{"key":"47030_CR23","doi-asserted-by":"publisher","first-page":"1376","DOI":"10.1016\/j.jtho.2017.05.011","volume":"12","author":"R Wan","year":"2017","unstructured":"Wan, R. et al. Comprehensive Analysis of the Discordance of EGFR Mutation Status between Tumor Tissues and Matched Circulating Tumor DNA in Advanced Non-Small Cell Lung Cancer. J Thorac Oncol 12, 1376\u20131387 (2017).","journal-title":"J Thorac Oncol"},{"issue":"Suppl 1","key":"47030_CR24","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1136\/ijgc-00009577-200505001-00008","volume":"15","author":"A Du Bois","year":"2005","unstructured":"Du Bois, A. & Pfisterer, J. Future options for first-line therapy of advanced ovarian cancer. Int J Gynecol Cancer 15(Suppl 1), 42\u201350 (2005).","journal-title":"Int J Gynecol Cancer"},{"key":"47030_CR25","doi-asserted-by":"publisher","first-page":"2473","DOI":"10.1056\/NEJMoa1104390","volume":"365","author":"RA Burger","year":"2011","unstructured":"Burger, R. A. et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med 365, 2473\u20132483 (2011).","journal-title":"N Engl J Med"},{"key":"47030_CR26","doi-asserted-by":"publisher","first-page":"852","DOI":"10.1016\/S1470-2045(14)70228-1","volume":"15","author":"J Ledermann","year":"2014","unstructured":"Ledermann, J. et al. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol 15, 852\u2013861 (2014).","journal-title":"Lancet Oncol"},{"key":"47030_CR27","doi-asserted-by":"publisher","first-page":"5","DOI":"10.3322\/caac.21254","volume":"65","author":"RL Siegel","year":"2015","unstructured":"Siegel, R. L., Miller, K. D. & Jemal, A. Cancer statistics, 2015, CA. Cancer J Clin 65, 5\u201329 (2015).","journal-title":"Cancer J Clin"},{"key":"47030_CR28","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1016\/j.ccell.2014.12.001","volume":"27","author":"N McGranahan","year":"2015","unstructured":"McGranahan, N. & Swanton, C. Biological and therapeutic impact of intratumor heterogeneity in cancer evolution. Cancer Cell 27, 15\u201326 (2015).","journal-title":"Cancer Cell"},{"key":"47030_CR29","doi-asserted-by":"publisher","first-page":"334","DOI":"10.1016\/j.ygyno.2017.05.038","volume":"146","author":"TKH Chung","year":"2017","unstructured":"Chung, T. K. H. et al. Liquid biopsy of PIK3CA mutations in cervical cancer in Hong Kong Chinese women. Gynecol Oncol 146, 334\u2013339 (2017).","journal-title":"Gynecol Oncol"},{"key":"47030_CR30","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/s41379-018-0158-8","volume":"32","author":"AM Bolivar","year":"2019","unstructured":"Bolivar, A. M. et al. Targeted next-generation sequencing of endometrial cancer and matched circulating tumor DNA: identification of plasma-based, tumor-associated mutations in early stage patients. Mod Pathol 32, 405\u2013414 (2019).","journal-title":"Mod Pathol"},{"key":"47030_CR31","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1200\/JCO.2017.75.3384","volume":"36","author":"H Rizvi","year":"2018","unstructured":"Rizvi, H. et al. Molecular Determinants of Response to Anti-Programmed Cell Death (PD)-1 and Anti-Programmed Death-Ligand 1 (PD-L1) Blockade in Patients With Non-Small-Cell Lung Cancer Profiled With Targeted Next-Generation Sequencing. J Clin Oncol 36, 633\u2013641 (2018).","journal-title":"J Clin Oncol"},{"key":"47030_CR32","doi-asserted-by":"publisher","first-page":"1441","DOI":"10.1038\/s41591-018-0134-3","volume":"24","author":"DR Gandara","year":"2018","unstructured":"Gandara, D. R. et al. Blood-based tumor mutational burden as a predictor of clinical benefit in non-small-cell lung cancer patients treated with atezolizumab. Nat Med 24, 1441\u20131448 (2018).","journal-title":"Nat Med"},{"key":"47030_CR33","doi-asserted-by":"publisher","first-page":"e100924","DOI":"10.1371\/journal.pone.0100924","volume":"9","author":"M Narahara","year":"2014","unstructured":"Narahara, M. et al. Large-scale East-Asian eQTL mapping reveals novel candidate genes for LD mapping and the genomic landscape of transcriptional effects of sequence variants. PLoS One 9, e100924 (2014).","journal-title":"PLoS One"},{"key":"47030_CR34","doi-asserted-by":"publisher","DOI":"10.1186\/s12864-016-3425-4","volume":"18","author":"C Xu","year":"2017","unstructured":"Xu, C., Nezami Ranjbar, M. R., Wu, Z., DiCarlo, J. & Wang, Y. Detecting very low allele fraction variants using targeted DNA sequencing and a novel molecular barcode-aware variant caller. BMC Genomics 18, 5 (2017).","journal-title":"BMC Genomics"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-47030-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-47030-w","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-47030-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,17]],"date-time":"2022-12-17T11:40:19Z","timestamp":1671277219000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-47030-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,7,18]]},"references-count":34,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["47030"],"URL":"https:\/\/doi.org\/10.1038\/s41598-019-47030-w","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,7,18]]},"assertion":[{"value":"28 February 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 July 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 July 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"10426"}}