Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) represent two major histological cancer subtypes confined within the liver. They are clinically and biologically heterogeneous, and are highly resistant to treatment, which makes them the second most lethal cancer for men in the world. In Thailand, liver cancer represents the primary cause of cancer-related death and is a major health problem, especially in north-eastern area of Thailand where liver fluke (O. viverrini) is endemic and approximately 70% of liver cancers are CCA. While HBV and HCV are major etiological factors for HCC globally, liver fluke infection is a major etiological factor for CCA in Thailand. These unique risk factor patterns provide an opportunity to study cancer heterogeneity and its unique 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 CCA susceptibility and progression. In a Phase I study, we determined molecular subtypes of HCC and CCA. We performed genomic profiling of 398 surgical specimens derived from 199 liver cancer patients. We employed the Affymetrix Human Transcriptome Array 2.0 to examine transcriptome profiles. Unsupervised Consensus Clustering (cCluster), Subclass Mapping (SM) and Gene Set Enrichment Analysis (GSEA) algorithms were used to analyze transcriptome data. The results were validated in 247 Asian HCC cases and 104 Caucasian CCA cases. We found that the Thai HCC cases consisted of 3 stable subgroups (C1-C3), while the Thai CCA cases contained 4 stable subgroups (C1-C4) based on gene expression patterns determined by cCluster. SM analysis revealed that CCA-C1 and HCC-C1 subtypes shared a similar gene expression matrix, as did CCA-C2 and HCC-C2 for a separate pattern. Interestingly, patients in both CCA-C1 and HCC-C1 had a poor prognosis, while those in CCA-C2 and HCC-C2 had a good prognosis. These prognostic subtypes were validated in an independent Asian HCC cohort but not in a Caucasian CCA cohort. GSEA revealed that among 17 significantly altered canonical pathways in the C1 subtype, 8 are related to mitotic checkpoint signaling. In contrast, the main signaling pathways associated with the C2 subtype were related to cytokine and chemokine signaling. We found that certain mitotic checkpoint genes are highly activated only in C1, but not in the C2 subtype. These results are consistent with the hypothesis that CCA and HCC from Asian populations consist of molecularly-similar tumor subgroups with similar prognostic impacts and unique tumor biology and that the C1 subtype may be sensitive to mitotic checkpoint blockage. Our ability to rigorously classify and validate both HCC and CCA using these tools may represent a new avenue for the development of targeted therapeutic interventions.
Citation Format: The TIGER-LC Consortium, Jittiporn Chaisaingmongkol, Anuradha Budhu, Hien Dang, Siritida Rabibhadana, Benjarath Pupacdi, Marshonna Forgues, 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, 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 for liver cancer (TIGER-LC): Defining novel subtypes of hepatocellular carcinoma and cholangiocarcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-173. doi:10.1158/1538-7445.AM2015-LB-173