Common molecular subtypes among Asian hepatocellular carcinoma and cholangiocarcinoma

Jittiporn Chaisaingmongkol, Anuradha Budhu, 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, Kris Ylaya, Xiaolin Wu, Jesper B. Andersen, Snorri S. Thorgeirsson, Joshua J. Waterfall, Yuelin J. Zhu, Jennifer Walling, Holly S. Stevenson, Daniel Edelman, Paul S. Meltzer, Christopher A. Loffredo, Natsuko Hama, Tatsuhiro Shibata, Robert H. Wiltrout, Curtis C. Harris, Chulabhorn Mahidol, Mathuros Ruchirawat, Xinwei Wang


Objective: Intrahepatic cholangiocarcinoma (ICC) andhepatocellular carcinoma (HCC) are clinically disparate primaryliver cancers with etiological and biological heterogeneity. InThailand, both cancer types represent the primary cause of cancer-related deaths and are a major public health concern.The Thailand Initiative in Genomics and Expression Researchfor Liver Cancer (TIGER-LC) consortium was established toidentify genomic and expression factors that may modify HCCand cholangiocarcinoma (CCA) susceptibility and progression.In a phase 1 study, we determined the molecular subtypesand features of HCC and CCA through system integration ofgenomic, transcriptomic, and metabolic profiles.

Methods: Genome-wide profiling of surgical specimens from199 Thai liver cancer patients was performed. The AffymetrixHuman Transcriptome Array 2.0, the Affymetrix Genome-WideHuman SNP Array 6.0, Metabolon's Discovery HD4 platform,and whole exome sequencing were used to generate integrativedata for further analysis. Unsupervised Consensus Clustering(cCluster), Subclass Mapping (SM), Gene Set EnrichmentAnalysis (GSEA), class comparison, loss of heterozygosity andminimum segmentation, and Pearson and rank correlationalalgorithms were used to analyze omics data. The results werevalidated in 852 independent Asian or Caucasian HCC orCCA cases.

Results: We identified common molecular subtypes linkedto similar prognosis among 199 Thai ICC and HCC patientsthrough systems integration of genomics, transcriptomics,and metabolomics. While ICC and HCC share recurrentlymutated genes, including TP53, ARID1A, and ARID2, mitoticcheckpoint anomalies distinguish the C1 subtype with the keydrivers PLK1 and ECT2, whereas the C2 subtype is linked toobesity, T cell infiltration, and bile acid metabolism. Thesemolecular subtypes were found in 582 Asian patients, but lessso in 265 Caucasian patients.

Conclusions: Asian ICC and HCC, while clinically treatedas separate entities, share common molecular subtypes withsimilar actionable drivers to improve precision therapy.

DOI: 10.20892/j.issn.2095-3941.2018.S077


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