Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are two distinct histological liver cancers. They are clinically and biologically heterogeneous and highly resistant to treatment, making liver cancer the second most lethal malignancy in the world. In Thailand, liver cancer represents the primary cause of cancer-related death and is a major health problem. While HBV and HCV are major etiological factors for HCC globally, liver fluke infection (O. viverrini) is a major etiological factor for ICC in Thailand, especially in north-eastern Thailand where O. viverrini is endemic and approximately 70% of liver cancers are ICC. These unique risk factor patterns provide an opportunity to study cancer heterogeneity and unique liver tumor biology. The Thailand Initiative in Genomics and Expression Research for Liver Cancer (TIGER-LC) consortium was established to identify genomic and expression factors that may modify HCC and ICC susceptibility and progression. Here, we determined molecular subtypes and features of HCC and ICC through systems integration of genomic, transcriptomic and metabolic profiles.
We performed genome wide profiling of 398 surgical specimens derived from 199 Thai liver cancer patients. We employed the Affymetrix Human Transcriptome Array 2.0, the Affymetrix Genome-Wide Human SNP Array 6.0, Metabolon's DiscoveryHD4 platform and Exome Sequencing to examine transcriptome profiles, somatic copy number alterations (SCNA), cancer metabolic profiles and mutation patterns, respectively. The results were validated in 847 independent Asian or Caucasian HCC or ICC cases.
Transcriptomic analyses revealed that Thai HCC consisted of 3 stable subgroups (C1-C3), while Thai ICC contained 4 stable subgroups (C1-C4). Interestingly, HCC-C1 and ICC-C1 subtypes shared a similar gene expression matrix, as did HCC-C2 and ICC-C2, which correlated with patient survival. These prognostic subtypes were validated in independent Asian HCC and ICC cohorts, but not in Caucasian patients, and were associated with tumor biology rather than etiology. GSEA revealed that the C1 subtype is enriched for mitotic checkpoint anomalies, while the C2 subtype is related to cytokine and chemokine signaling. We found that the C1 subtype encompassed a higher degree of SCNA when compared to the C2 subtype, suggesting an association with a genomic instability phenotype. Further analysis showed that the C2 subtype is linked to an increased body mass index, inflammatory responses and unique tumor metabolic activities.
HCC and ICC from Asian populations, while clinically treated as separate entities, share common subtypes with similar actionable drivers which can be targeted to improve precision therapy.
Citation Format: Anuradha Budhu, Jittiporn Chaisaingmongkol, Hien Dang, Siritida Rabibhadana, Benjarath Pupacdi, So Mee Kwon, Marshonna Forgues, Yotsawat Pomyen, Vajarabhongsa Bhudhisawasdi, Nirush Lertprasertsuke, Anon Chotirosniramit, Chawalit Pairojkul, Chirayu U. Auewarakul, Thaniya Sricharunrat, Kannika Phornphutkul, Suleeporn Sangrajrang, Maggie Cam, Ping He, Stephen M. Hewitt, Xiaolin Wu, Snorri S. Thorgeirsson, Joshua J. Waterfall, Yuelin J. Zhu, Jennifer Walling, Holly S. Stevenson, Daniel Edelman, Paul S. Meltzer, Christopher A. Loffredo, Robert H. Wiltrout, Curtis C. Harris, Chulabhorn Mahidol, Mathuros Ruchirawat, Xin W. Wang. The Thailand initiative in genomics and expression research in liver cancer: Race related common molecular subtypes among Asian hepatocellular carcinoma and cholangiocarcinoma identified by integrated genomics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4390. doi:10.1158/1538-7445.AM2017-4390