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Article

Molecular Classification and Tumor Microenvironment Characterization of Gallbladder Cancer by Comprehensive Genomic and Transcriptomic Analysis

1
Laboratory for Cancer Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan
2
Department of Gastroenterological Surgery II, Faculty of Medicine, Hokkaido University, Sapporo 060-8638, Japan
3
Research Division of Companion Diagnostics, Hokkaido University Hospital, Sapporo 060-8638, Japan
4
Department of Surgical Pathology, Hokkaido University Hospital, Hokkaido 060-8648, Japan
5
Laboratory of DNA Information Analysis, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
*
Authors to whom correspondence should be addressed.
Academic Editor: David Wong
Cancers 2021, 13(4), 733; https://doi.org/10.3390/cancers13040733
Received: 12 January 2021 / Revised: 19 January 2021 / Accepted: 2 February 2021 / Published: 10 February 2021
(This article belongs to the Special Issue Genome Informatics and Cancers)
Gallbladder cancer (GBC) is a rare but lethal cancer. Molecular characterization of GBC is insufficient so far, and a comprehensive molecular portrait is warranted to uncover new targets and classify GBC. Clustering analysis of RNA expression revealed two subclasses of 36 GBCs, which reflects the status of the tumor microenvironment (TME) and poor prognosis of GBC, including epithelial–mesenchymal transition (EMT), immune suppression, and the TGF-β signaling pathway. The knockout of miR125B1 in GBC cell lines decreased its invasion ability and altered the EMT pathway. Mutations of the genes related to the TGF-β signaling pathway were enriched in the poor-prognosis/TME-rich cluster of GBCs. This comprehensive molecular analysis provides a new classification of GBCs based on the TME activity, which is involved with EMT and immune suppression for poor prognosis of GBC. This information may be useful for GBC prognosis and therapeutic decision-making.
Gallbladder cancer (GBC), a rare but lethal disease, is often diagnosed at advanced stages. So far, molecular characterization of GBC is insufficient, and a comprehensive molecular portrait is warranted to uncover new targets and classify GBC. We performed a transcriptome analysis of both coding and non-coding RNAs from 36 GBC fresh-frozen samples. The results were integrated with those of comprehensive mutation profiling based on whole-genome or exome sequencing. The clustering analysis of RNA-seq data facilitated the classification of GBCs into two subclasses, characterized by high or low expression levels of TME (tumor microenvironment) genes. A correlation was observed between gene expression and pathological immunostaining. TME-rich tumors showed significantly poor prognosis and higher recurrence rate than TME-poor tumors. TME-rich tumors showed overexpression of genes involved in epithelial-to-mesenchymal transition (EMT) and inflammation or immune suppression, which was validated by immunostaining. One non-coding RNA, miR125B1, exhibited elevated expression in stroma-rich tumors, and miR125B1 knockout in GBC cell lines decreased its invasion ability and altered the EMT pathway. Mutation profiles revealed TP53 (47%) as the most commonly mutated gene, followed by ELF3 (13%) and ARID1A (11%). Mutations of ARID1A, ERBB3, and the genes related to the TGF-β signaling pathway were enriched in TME-rich tumors. This comprehensive analysis demonstrated that TME, EMT, and TGF-β pathway alterations are the main drivers of GBC and provides a new classification of GBCs that may be useful for therapeutic decision-making. View Full-Text
Keywords: gallbladder cancer; tumor microenvironment; EMT; TGF-β signaling pathway gallbladder cancer; tumor microenvironment; EMT; TGF-β signaling pathway
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MDPI and ACS Style

Ebata, N.; Fujita, M.; Sasagawa, S.; Maejima, K.; Okawa, Y.; Hatanaka, Y.; Mitsuhashi, T.; Oosawa-Tatsuguchi, A.; Tanaka, H.; Miyano, S.; Nakamura, T.; Hirano, S.; Nakagawa, H. Molecular Classification and Tumor Microenvironment Characterization of Gallbladder Cancer by Comprehensive Genomic and Transcriptomic Analysis. Cancers 2021, 13, 733. https://doi.org/10.3390/cancers13040733

AMA Style

Ebata N, Fujita M, Sasagawa S, Maejima K, Okawa Y, Hatanaka Y, Mitsuhashi T, Oosawa-Tatsuguchi A, Tanaka H, Miyano S, Nakamura T, Hirano S, Nakagawa H. Molecular Classification and Tumor Microenvironment Characterization of Gallbladder Cancer by Comprehensive Genomic and Transcriptomic Analysis. Cancers. 2021; 13(4):733. https://doi.org/10.3390/cancers13040733

Chicago/Turabian Style

Ebata, Nobutaka, Masashi Fujita, Shota Sasagawa, Kazuhiro Maejima, Yuki Okawa, Yutaka Hatanaka, Tomoko Mitsuhashi, Ayako Oosawa-Tatsuguchi, Hiroko Tanaka, Satoru Miyano, Toru Nakamura, Satoshi Hirano, and Hidewaki Nakagawa. 2021. "Molecular Classification and Tumor Microenvironment Characterization of Gallbladder Cancer by Comprehensive Genomic and Transcriptomic Analysis" Cancers 13, no. 4: 733. https://doi.org/10.3390/cancers13040733

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