LAUSR

Background & Aim: Intrahepatic cholangiocarcinoma(ICC) accounts for about 5% of all primary liver cancer and is reported to be common in Southeast Asia and parts of Chile, but in recent years it has been increasing in other areas including Europe and the United States. ICC leads to a dismal outcome as the commonly used chemotherapy exhibit purely palliative effects on ICC, enabling only a limited improvement in survival until today. As ICC harbors few actionable target genes with inter-tumor genomic heterogeneity, ICC is considered to be one of the most intractable malignancies of all. Therefore, we implemented the multi-omics analysis especially with comprehension of the oncogenic metabolic changes to confer new treatment strategies. This study aims to unravel the evolution of ICC and identify ICC-specific metabolic pathways and essential targets for eradicating ICC. Approach: We collected 12 primary ICC cases and 77 specimens and conducted a multi-omics approach, including genomics, transcriptomics, proteomics, and metabolomics for each material. Results: We demonstrated that intra-tumoral heterogeneity of ICCs with distinct driver genes per case indicates a “neutral evolution manner”, regardless of their tumor stage. Upregulation of BCAT1 and BCAT2 might enrich the ‘branched-chain amino acids (BCAA), such as Val, Leu, and Ile degradation pathway’. ICCs cases with the accumulated ubiquitous metabolites, BCAA exhibited poorer prognosis than those cases without BCAA accumulation significantly. Conclusions: Regardless of the inter-tumor heterogeneity in genomic aberrations among ICC cases, we discovered the ubiquitous enrichment of the BCAA metabolic pathway in each tumor. We propose a novel ICC onco-metabolic pathway that could enable the development of new therapeutic interventions. Citation Format: Yusuke Nakano, Akihiro Kitagawa, Masahiro Hashimoto, Tadashi Abe, Yuichi Hisamatsu, Takeo Toshima, Yusuke Yonemura, Takaaki Masuda, Akira Inoue, Hidetoshi Eguchi, Yuichiro Doki, Koshi Mimori. Convergent genomic diversity and novel oncogenic metabolism in intrahepatic cholangiocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 101.