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

• Published in: Cancers Vol. 13; no. 4; p. 733
• Main Authors: Ebata, Nobutaka, Fujita, Masashi, Sasagawa, Shota, Maejima, Kazuhiro, Okawa, Yuki, Hatanaka, Yutaka, Mitsuhashi, Tomoko, Oosawa-Tatsuguchi, Ayako, Tanaka, Hiroko, Miyano, Satoru, Nakamura, Toru, Hirano, Satoshi, Nakagawa, Hidewaki
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI 10.02.2021; MDPI AG
• Subjects: EMT; gallbladder cancer; TGF-β signaling pathway; tumor microenvironment; gallbladder cancer; tumor microenvironment; TGF-β signaling pathway; EMT
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers13040733

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, , exhibited elevated expression in stroma-rich tumors, and knockout in GBC cell lines decreased its invasion ability and altered the EMT pathway. Mutation profiles revealed (47%) as the most commonly mutated gene, followed by (13%) and (11%). Mutations of , , 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.