• Shuichi Mitsunaga, Masafumi Ikeda, Makoto Ueno, Satoshi Kobayshi, Masahiro Tsuda, Ikuya Miki, Takamichi Kuwahara, Kazuo Hara, Yukiko Takayama, Yutaro Matsunaga, Keiji Hanada, Akinori Shimizu, Hitoshi Yoshida, Tomohiro Nomoto, Kenji Takahashi, Hidetaka Iwamoto, Hideaki Iwama, Etsuro Hatano, Kohei Nakata, Masafumi Nakamura, Hiroko Sudo, Satoko Takizawa, and Atsushi Ochiai.
• Division of Biomarker Discovery, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan. smitsuna@east.ncc.go.jp.
• Bmc Med. 2025 Jan 21; 23 (1): 2323.

BackgroundA new circulating biomarker superior to carbohydrate antigen 19-9 (CA19-9) is needed for diagnosing pancreatobiliary cancer (PBca). The aim of this study was to identify serum microRNA (miRNA) signatures comprising reproducible and disease-related miRNAs.MethodsThis multicenter study involved patients with treatment-naïve PBca and healthy participants. The optimized serum processing conditions were evaluated using t-distributed stochastic neighbor embedding (t-SNE) visualization. Serum miRNA candidates for disease association were selected using weighted gene coexpression network analysis (WGCNA). A miRNA signature combining multiple serum miRNAs was tested in exploratory, validation, and independent validation sets. The synthesis and secretion of diagnostic miRNAs were evaluated using human pancreatic cancer cells.ResultsIn total, 284 (150 healthy and 134 PBca) of 827 serum samples were processed within 2 h of blood collection before freezing, distributed in the same area as that in the t-SNE map, and assigned to an exploratory set. The 193 optimized samples were assigned to either the validation (50 healthy, 47 PBca) or independent validation (50 healthy, 46 PBca) set. Index-1, a combination of five serum miRNAs (hsa-miR-1343-5p, hsa-miR-4632-5p, hsa-miR-4665-5p, hsa-miR-665, and hsa-miR-6803-5p) with disease association in WGCNA, showed a sensitivity and specificity of > 80% and an AUC outperforming that of CA19-9 in the exploratory, validation, and independent validation sets. The AUC of Index-1 was superior to that of CA19-9 (0.856 vs. 0.649, p = 0.038) for detecting T1 tumors. miR-665, a component of Index-1, was expressed in human pancreatic cancer cells, and its transfection inhibited cell growth.ConclusionsThe serum miRNA signature Index-1 is useful for detecting PBca and could facilitate the early diagnosis of PBca. These findings can help improve clinical PBca detection by providing an optimized biomarker that overcomes the limitations of the current standard.© 2025. The Author(s).

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