Abstract IA40: Race-related liver tumor subtypes are associated with gut microbiome-mediated metabolism

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Abstract Liver cancer has one of the fastest-rising incidence rates in the United States and across the world. It disproportionally affects men and individuals of Asian and African descent. Liver cancer consists of two main histologically distinct subtypes, i.e., hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA) confined within the liver, whose diagnoses and treatment decisions are uniquely based on their baseline clinical features. However, both HCC and iCCA are genetically, etiologically, and biologically heterogeneous, and have a complex mutational landscape with vast intertumor and intratumor heterogeneity, which poses a major challenge to define actionable drivers. With the need of a well-annotated biobank to improve our understanding of disease susceptibility, progression, and outcome at a global level, we established the Thailand Initiative in Genomics and Expression Research for Liver Cancer (TIGER-LC) consortium to create a comprehensive biorepository with biospecimens linked to etiologies and clinical features from 3,000 patients with liver cancer and 3,000 high-risk and healthy individuals who reside in Thailand. Here, by characterizing the first 199 sequentially enrolled Thai patients, we could demonstrate the presence of common molecular subtypes among HCC and iCCA patients in Thailand using state-of-the-art systems integration of genomics, transcriptomics, and metabolomics. While HCC and iCCA share recurrently mutated genes (TP53, ARID1A, and ARID2), mitotic checkpoint anomalies distinguish the C1 subtype with key drivers PLK1 and ECT2 from the C2 subtype, which is mainly linked to obesity, T-cell infiltration, and gut microbiome-mediated bile acid metabolism. Intriguingly, however, certain molecular subtypes were found in Asian, but less so in Caucasian, patients in our study, indicating geographic differences in disease presentation. Notably, Thai patients with the common C2 subtype showed elevated serum microbial metabolites, consistent with a potential effect of the local microbiome on tumor biology. In support of this hypothesis, we could demonstrate that gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells in mice. Thus, HCC and iCCA, while clinically treated as separate entities, shared common molecular subtypes with similar actionable drivers and underlying tumor biology in an Asian patient population. However, our study also provides evidence of geographic disease heterogeneity and a rationale for liver cancer intervention based on regulating the balance of gut microflora. Citation Format: Xin W. Wang, Anuradha Budhu, Jittiporn Chaisaingmongkol, Yotsawat Pomyen, Mathuros Ruchirawat, Tim F. Greten. Race-related liver tumor subtypes are associated with gut microbiome-mediated metabolism [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr IA40.