Identification of highly sensitive biomarkers that can aid the early detection of pancreatic cancer using GC/MS/MS-based targeted metabolomics

Yuichi Hirata; Takashi Kobayashi; Shin Nishiumi; Kodai Yamanaka; Takashi Nakagawa; Seiji Fujigaki; Takao Iemoto; Makoto Kobayashi; Takuji Okusaka; Shoji Nakamori; Masashi Shimahara; Takaaki Ueno; Akihiko Tsuchida; Naohiro Sata; Tatsuya Ioka; Yohichi Yasunami; Tomoo Kosuge; Takashi Kaneda; Takao Kato; Kazuhiro Yagihara; Shigeyuki Fujita; Tesshi Yamada; Kazufumi Honda; Takeshi Azuma; Masaru Yoshida

doi:10.1016/j.cca.2017.02.011

Identification of highly sensitive biomarkers that can aid the early detection of pancreatic cancer using GC/MS/MS-based targeted metabolomics

Clin Chim Acta. 2017 May:468:98-104. doi: 10.1016/j.cca.2017.02.011. Epub 2017 Feb 16.

Authors

Yuichi Hirata¹, Takashi Kobayashi¹, Shin Nishiumi¹, Kodai Yamanaka¹, Takashi Nakagawa¹, Seiji Fujigaki¹, Takao Iemoto¹, Makoto Kobayashi², Takuji Okusaka³, Shoji Nakamori⁴, Masashi Shimahara⁵, Takaaki Ueno⁵, Akihiko Tsuchida⁶, Naohiro Sata⁷, Tatsuya Ioka⁸, Yohichi Yasunami⁹, Tomoo Kosuge¹⁰, Takashi Kaneda¹¹, Takao Kato¹², Kazuhiro Yagihara¹³, Shigeyuki Fujita¹⁴, Tesshi Yamada², Kazufumi Honda¹⁵, Takeshi Azuma¹, Masaru Yoshida¹⁶

Affiliations

¹ Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Hyogo, Japan.
² Division of Chemotherapy and Clinical Research, National Cancer Center Research Institute, Tokyo, Japan.
³ Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan.
⁴ Departments of Hepato-Biliary-Pancreatic Surgery, Osaka National Hospital, National Hospital Organization, Osaka, Japan.
⁵ Department of Oral Surgery, Osaka Medical College, Osaka, Japan.
⁶ Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, Tokyo, Japan.
⁷ Department of Surgery, Jichi Medical University, Tochigi, Japan.
⁸ Department of GI Cancer Screening and Surveillance, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.
⁹ Islet Institute, Fukuoka University, Fukuoka, Japan.
¹⁰ Department of Gastrointestinal Surgery, JR Tokyo General Hospital, Tokyo, Japan.
¹¹ Department of Radiology, Nihon University School of Dentistry at Matsudo, Chiba, Japan.
¹² Department of Oral Implant, Nihon University School of Dentistry at Matsudo, Chiba, Japan.
¹³ Department of Oral Surgery, Saitama Cancer Center, Saitama, Japan.
¹⁴ Department of Oral and Maxillofacial Surgery, Wakayama Medical University, Wakayama, Japan.
¹⁵ Division of Chemotherapy and Clinical Research, National Cancer Center Research Institute, Tokyo, Japan; Japan Agency for Medical Research and Development (AMED) CREST, Tokyo, Japan.
¹⁶ Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Hyogo, Japan; Metabolomics Research, Department of Internal Related, Kobe University Graduate School of Medicine, Hyogo, Japan; AMED-CREST, AMED, Hyogo, Japan. Electronic address: [email protected].

PMID: 28215548
DOI: 10.1016/j.cca.2017.02.011

Abstract

Background: To improve prognosis of pancreatic cancer (PC) patients, the discovery of more reliable biomarkers for the early detection is desired.

Methods: Blood samples were collected by 2 independent groups. The 1st set was included 55 early PC and 58 healthy volunteers (HV), and the 2nd set was included 16 PC and 16HV. The 16 targeted metabolites were quantitatively analyzed by gas chromatography/tandem mass spectrometry together with their corresponding stable isotopes. In the 1st set, the levels of these metabolites were evaluated, and diagnostic models were constructed via multivariate logistic regression analysis, leading to validation using the 2nd set.

Results: In the 1st set, model X consisting of 4 candidates based on our previous report possessed higher sensitivity (74.1%) than carbohydrate antigen 19-9 (CA19-9). Model Y, consisting of 2 metabolites newly selected from 16 metabolites via stepwise method possessed higher sensitivity (70.4%) than CA19-9. Furthermore, combining model Y with CA19-9 increased its sensitivity (90.7%) and specificity (89.5%). In the 2nd set, combining model Y with CA19-9 displayed high sensitivity (81.3%) and specificity (93.8%). In particular, it displayed very high sensitivity (100%) for resectable PC.

Conclusions: Quantitative analysis confirmed that metabolomics-based diagnostic methods are useful for detecting PC early.

Keywords: Biomarker; Early detection; GC/MS/MS; Metabolomics; Pancreatic cancer.

MeSH terms

Aged
Aged, 80 and over
Biomarkers, Tumor / blood*
Biomarkers, Tumor / metabolism
Early Detection of Cancer / methods*
Female
Gas Chromatography-Mass Spectrometry*
Humans
Male
Metabolomics*
Middle Aged
Pancreatic Neoplasms / blood*
Pancreatic Neoplasms / diagnosis*
Pancreatic Neoplasms / metabolism
Tandem Mass Spectrometry*

Substances

Biomarkers, Tumor