Clinical utility of circulating tumor DNA for molecular assessment in pancreatic cancer

Erina Takai; Yasushi Totoki; Hiromi Nakamura; Chigusa Morizane; Satoshi Nara; Natsuko Hama; Masami Suzuki; Eisaku Furukawa; Mamoru Kato; Hideyuki Hayashi; Takashi Kohno; Hideki Ueno; Kazuaki Shimada; Takuji Okusaka; Hitoshi Nakagama; Tatsuhiro Shibata; Shinichi Yachida

doi:10.1038/srep18425

Clinical utility of circulating tumor DNA for molecular assessment in pancreatic cancer

Erina Takai, Yasushi Totoki, Hiromi Nakamura, Chigusa Morizane, Satoshi Nara, Natsuko Hama, Masami Suzuki, Eisaku Furukawa, Mamoru Kato, Hideyuki Hayashi, Takashi Kohno, Hideki Ueno, Kazuaki Shimada, Takuji Okusaka, Hitoshi Nakagama, Tatsuhiro Shibata, Shinichi Yachida

Research output: Contribution to journal › Article › peer-review

146 Citations (Scopus)

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies. The genomic landscape of the PDAC genome features four frequently mutated genes (KRAS, CDKN2A, TP53, and SMAD4) and dozens of candidate driver genes altered at low frequency, including potential clinical targets. Circulating cell-free DNA (cfDNA) is a promising resource to detect and monitor molecular characteristics of tumors. In the present study, we determined the mutational status of KRAS in plasma cfDNA using multiplex picoliter-droplet digital PCR in 259 patients with PDAC. We constructed a novel modified SureSelect-KAPA-Illumina platform and an original panel of 60 genes. We then performed targeted deep sequencing of cfDNA and matched germline DNA samples in 48 patients who had ≥ 1% mutant allele frequencies of KRAS in plasma cfDNA. Importantly, potentially targetable somatic mutations were identified in 14 of 48 patients (29.2%) examined by targeted deep sequencing of cfDNA. We also analyzed somatic copy number alterations based on the targeted sequencing data using our in-house algorithm, and potentially targetable amplifications were detected. Assessment of mutations and copy number alterations in plasma cfDNA may provide a prognostic and diagnostic tool to assist decisions regarding optimal therapeutic strategies for PDAC patients.

Original language	English
Article number	18425
Journal	Scientific reports
Volume	5
DOIs	https://doi.org/10.1038/srep18425
Publication status	Published - 2015 Dec 16
Externally published	Yes

ASJC Scopus subject areas

General

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/srep18425

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Takai, E., Totoki, Y., Nakamura, H., Morizane, C., Nara, S., Hama, N., Suzuki, M., Furukawa, E., Kato, M., Hayashi, H., Kohno, T., Ueno, H., Shimada, K., Okusaka, T., Nakagama, H., Shibata, T., & Yachida, S. (2015). Clinical utility of circulating tumor DNA for molecular assessment in pancreatic cancer. Scientific reports, 5, Article 18425. https://doi.org/10.1038/srep18425

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title = "Clinical utility of circulating tumor DNA for molecular assessment in pancreatic cancer",

abstract = "Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies. The genomic landscape of the PDAC genome features four frequently mutated genes (KRAS, CDKN2A, TP53, and SMAD4) and dozens of candidate driver genes altered at low frequency, including potential clinical targets. Circulating cell-free DNA (cfDNA) is a promising resource to detect and monitor molecular characteristics of tumors. In the present study, we determined the mutational status of KRAS in plasma cfDNA using multiplex picoliter-droplet digital PCR in 259 patients with PDAC. We constructed a novel modified SureSelect-KAPA-Illumina platform and an original panel of 60 genes. We then performed targeted deep sequencing of cfDNA and matched germline DNA samples in 48 patients who had ≥ 1% mutant allele frequencies of KRAS in plasma cfDNA. Importantly, potentially targetable somatic mutations were identified in 14 of 48 patients (29.2%) examined by targeted deep sequencing of cfDNA. We also analyzed somatic copy number alterations based on the targeted sequencing data using our in-house algorithm, and potentially targetable amplifications were detected. Assessment of mutations and copy number alterations in plasma cfDNA may provide a prognostic and diagnostic tool to assist decisions regarding optimal therapeutic strategies for PDAC patients.",

author = "Erina Takai and Yasushi Totoki and Hiromi Nakamura and Chigusa Morizane and Satoshi Nara and Natsuko Hama and Masami Suzuki and Eisaku Furukawa and Mamoru Kato and Hideyuki Hayashi and Takashi Kohno and Hideki Ueno and Kazuaki Shimada and Takuji Okusaka and Hitoshi Nakagama and Tatsuhiro Shibata and Shinichi Yachida",

note = "Funding Information: We thank Dr Koh Furuta (National Cancer Center Hospital) and Ms Kaho Minoura (Agilent Technologies) for technical advice, Ms Shoko Ohashi and Ms Keiko Igarashi (National Cancer Center Research Institute) for technical assistance and Ms Hiroko Hosoi (National Cancer Center Hospital) for clinical contributions. This work was supported by grants from the following: the National Cancer Center Research and Development Fund (25-A-3 to S.Y.; 26-A-5 to T.S.); the Takeda Science Foundation (S.Y.); Grants-in Aid for Scientific Research from the Ministry of Education, Science and Culture of Japan (26870874 to E.T.; 25134719 and 26670613 to S.Y.); the Ministry of Health Labour and Welfare (Health and Labour Sciences Research Expenses for Commission and Applied Research for Innovative Treatment of Cancer (to E.T., C.M., M.K., T.O., T.S. and S.Y.); the Medical Research Encouragement Prize of the Japan Medical Association (S.Y.). The National Cancer Center Biobank is supported by the National Cancer Center Research and Development Fund, Japan. The super-computing resource “SHIROKANE” was provided by the Human Genome Center, The University of Tokyo (http://sc.hgc.jp/shirokane.html).",

year = "2015",

month = dec,

day = "16",

doi = "10.1038/srep18425",

language = "English",

volume = "5",

journal = "Scientific reports",

issn = "2045-2322",

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T1 - Clinical utility of circulating tumor DNA for molecular assessment in pancreatic cancer

AU - Takai, Erina

AU - Totoki, Yasushi

AU - Nakamura, Hiromi

AU - Morizane, Chigusa

AU - Nara, Satoshi

AU - Hama, Natsuko

AU - Suzuki, Masami

AU - Furukawa, Eisaku

AU - Kato, Mamoru

AU - Hayashi, Hideyuki

AU - Kohno, Takashi

AU - Ueno, Hideki

AU - Shimada, Kazuaki

AU - Okusaka, Takuji

AU - Nakagama, Hitoshi

AU - Shibata, Tatsuhiro

AU - Yachida, Shinichi

N1 - Funding Information: We thank Dr Koh Furuta (National Cancer Center Hospital) and Ms Kaho Minoura (Agilent Technologies) for technical advice, Ms Shoko Ohashi and Ms Keiko Igarashi (National Cancer Center Research Institute) for technical assistance and Ms Hiroko Hosoi (National Cancer Center Hospital) for clinical contributions. This work was supported by grants from the following: the National Cancer Center Research and Development Fund (25-A-3 to S.Y.; 26-A-5 to T.S.); the Takeda Science Foundation (S.Y.); Grants-in Aid for Scientific Research from the Ministry of Education, Science and Culture of Japan (26870874 to E.T.; 25134719 and 26670613 to S.Y.); the Ministry of Health Labour and Welfare (Health and Labour Sciences Research Expenses for Commission and Applied Research for Innovative Treatment of Cancer (to E.T., C.M., M.K., T.O., T.S. and S.Y.); the Medical Research Encouragement Prize of the Japan Medical Association (S.Y.). The National Cancer Center Biobank is supported by the National Cancer Center Research and Development Fund, Japan. The super-computing resource “SHIROKANE” was provided by the Human Genome Center, The University of Tokyo (http://sc.hgc.jp/shirokane.html).

PY - 2015/12/16

Y1 - 2015/12/16

N2 - Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies. The genomic landscape of the PDAC genome features four frequently mutated genes (KRAS, CDKN2A, TP53, and SMAD4) and dozens of candidate driver genes altered at low frequency, including potential clinical targets. Circulating cell-free DNA (cfDNA) is a promising resource to detect and monitor molecular characteristics of tumors. In the present study, we determined the mutational status of KRAS in plasma cfDNA using multiplex picoliter-droplet digital PCR in 259 patients with PDAC. We constructed a novel modified SureSelect-KAPA-Illumina platform and an original panel of 60 genes. We then performed targeted deep sequencing of cfDNA and matched germline DNA samples in 48 patients who had ≥ 1% mutant allele frequencies of KRAS in plasma cfDNA. Importantly, potentially targetable somatic mutations were identified in 14 of 48 patients (29.2%) examined by targeted deep sequencing of cfDNA. We also analyzed somatic copy number alterations based on the targeted sequencing data using our in-house algorithm, and potentially targetable amplifications were detected. Assessment of mutations and copy number alterations in plasma cfDNA may provide a prognostic and diagnostic tool to assist decisions regarding optimal therapeutic strategies for PDAC patients.

AB - Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies. The genomic landscape of the PDAC genome features four frequently mutated genes (KRAS, CDKN2A, TP53, and SMAD4) and dozens of candidate driver genes altered at low frequency, including potential clinical targets. Circulating cell-free DNA (cfDNA) is a promising resource to detect and monitor molecular characteristics of tumors. In the present study, we determined the mutational status of KRAS in plasma cfDNA using multiplex picoliter-droplet digital PCR in 259 patients with PDAC. We constructed a novel modified SureSelect-KAPA-Illumina platform and an original panel of 60 genes. We then performed targeted deep sequencing of cfDNA and matched germline DNA samples in 48 patients who had ≥ 1% mutant allele frequencies of KRAS in plasma cfDNA. Importantly, potentially targetable somatic mutations were identified in 14 of 48 patients (29.2%) examined by targeted deep sequencing of cfDNA. We also analyzed somatic copy number alterations based on the targeted sequencing data using our in-house algorithm, and potentially targetable amplifications were detected. Assessment of mutations and copy number alterations in plasma cfDNA may provide a prognostic and diagnostic tool to assist decisions regarding optimal therapeutic strategies for PDAC patients.

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Clinical utility of circulating tumor DNA for molecular assessment in pancreatic cancer

Abstract

ASJC Scopus subject areas

UN SDGs

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