title: Clinicopathological indices to predict hepatocellular carcinoma molecular classification.
abstract: OBJECTIVE
  Hepatocellular carcinoma (HCC) is the second most lethal cancer caused by lack of effective therapies. Although promising, HCC molecular classification, which enriches potential responders to specific therapies, has not yet been assessed in clinical trials of anti-HCC drugs. We aimed to overcome these challenges by developing clinicopathological surrogate indices of HCC molecular classification.
  
  
  METHODS
  Hepatocellular carcinoma classification defined in our previous transcriptome meta-analysis (S1, S2 and S3 subclasses) was implemented in an FDA-approved diagnostic platform (Elements assay, NanoString). Ninety-six HCC tumours (training set) were assayed to develop molecular subclass-predictive indices based on clinicopathological features, which were independently validated in 99 HCC tumours (validation set). Molecular deregulations associated with the histopathological features were determined by pathway analysis. Sample sizes for HCC clinical trials enriched with specific molecular subclasses were determined.
  
  
  RESULTS
  Hepatocellular carcinoma subclass-predictive indices were steatohepatitic (SH)-HCC variant and immune cell infiltrate for S1 subclass, macrotrabecular/compact pattern, lack of pseudoglandular pattern, and high serum alpha-foetoprotein (>400 ng/ml) for S2 subclass, and microtrabecular pattern, lack of SH-HCC and clear cell variants, and lower histological grade for S3 subclass. Macrotrabecular/compact pattern, a predictor of S2 subclass, was associated with the activation of therapeutically targetable oncogene YAP and stemness markers EPCAM/KRT19. BMP4 was associated with pseudoglandular pattern. Subclass-predictive indices-based patient enrichment reduced clinical trial sample sizes from 121, 184 and 53 to 30, 43 and 22 for S1, S2 and S3 subclass-targeting therapies respectively.
  
  
  CONCLUSIONS
  Hepatocellular carcinoma molecular subclasses can be enriched by clinicopathological indices tightly associated with deregulation of therapeutically targetable molecular pathways.
authors.affiliation: Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Division of Gastroenterology and Hepatology, University Medicine Cluster, National University Health System, Singapore, Singapore.
authors.forename: Poh Seng
authors.initials: PS
authors.lastname: Tan
authors.affiliation: Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Nakagawa
authors.affiliation: Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Division of Gastroenterology and Hepatology, Geneva University Hospital, Switzerland.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Goossens
authors.affiliation: Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Anu
authors.initials: A
authors.lastname: Venkatesh
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Tiangui
authors.initials: T
authors.lastname: Huang
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Ward
authors.affiliation: Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Xiaochen
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Won-Min
authors.initials: WM
authors.lastname: Song
authors.affiliation: Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Koh
authors.affiliation: Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Claudia
authors.initials: C
authors.lastname: Canasto-Chibuque
authors.affiliation: Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Manjeet
authors.initials: M
authors.lastname: Deshmukh
authors.affiliation: Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Venugopalan
authors.initials: V
authors.lastname: Nair
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Milind
authors.initials: M
authors.lastname: Mahajan
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Maria Isabel
authors.initials: MI
authors.lastname: Fiel
authors.affiliation: Department of Hepatology, Toranomon Hospital, Tokyo, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kobayashi
authors.affiliation: Department of Hepatology, Toranomon Hospital, Tokyo, Japan.
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Kumada
authors.affiliation: Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Yujin
authors.initials: Y
authors.lastname: Hoshida
mesh_terms: D000368:Aged; D000595:Amino Acid Sequence; D000951:Antigens, Neoplasm / Q000032:analysis*; D055415:Bone Morphogenetic Protein 4 / Q000032:analysis*; D006528:Carcinoma, Hepatocellular / Q000145:classification / Q000378:metabolism / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000032:analysis*; D055808:Drug Discovery; D000071858:Epithelial Cell Adhesion Molecule; D005260:Female; D020869:Gene Expression Profiling; D055106:Genome-Wide Association Study; D006801:Humans; D053539:Keratin-19 / Q000032:analysis*; D008113:Liver Neoplasms / Q000145:classification / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D060787:Neoplasm Grading; D011379:Prognosis; D000509:alpha-Fetoproteins / Q000032:analysis
chemical_list: D000951:Antigens, Neoplasm; C525809:BMP4 protein, human; D055415:Bone Morphogenetic Protein 4; D015815:Cell Adhesion Molecules; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule; D053539:Keratin-19; D000509:alpha-Fetoproteins
keywords: clinical diagnostic; gene expression; histopathology; molecular subclass; predictive index