title: Comprehensive multiplatform biomarker analysis of 350 hepatocellular carcinomas identifies potential novel therapeutic options.
abstract: OBJECTIVE
  Effective therapies for hepatocellular carcinoma (HCC) are limited. Molecular profiling of HCC was performed to identify novel therapeutic targets.
  
  
  METHODS
  350 HCC samples were evaluated using a multiplatform profiling service (Caris Life Sciences, Phoenix, AZ), including gene sequencing, amplification, and protein expression.
  
  
  RESULTS
  EGFR, TOPO1, PD-1, TOP2A, SPARC, and c-Met were overexpressed in 25-83% of samples. Decreased expression of RRM1,TS, PTEN, and MGMT occurred in 31-82% of samples. TP53 was mutated in 30%, CTNNB1 in 20%, and BRCA2 in 18%; other gene mutation rates were <5%. TP53-mutated tumors showed significantly higher TOPO2A (90% vs. 38%, P < 0.0001) and TS (56% vs. 29%, P = 0.0139) expression. CTNNB1-mutated tumors had significantly higher AR (56% vs. 21%, P = 0.0017), SPARC (61% vs. 29%, P = 0.0135), PDL1 (29% vs. 0%, P = 0.0256) expression, and BRCA2 mutations (50% vs. 6%, P = 0.0458). Metastases exhibited significantly higher infiltration by PD-1+ lymphocytes (79% vs. 50%, P = 0.047) and TS (31% vs. 14%, P < 0.0003) than primary HCC.
  
  
  CONCLUSIONS
  Multiplatform profiling reveals molecular heterogeneity in HCC and identifies potential therapies including tyrosine kinase, PI3 kinase, or PARP inhibitors for molecular subtypes. Chemotherapy may benefit some tumors. CTNNB1-mutated tumors may respond to multi-target inhibition. These limited and preliminary data require clinical validation.
authors.affiliation: Department of Medicine, Hematology/Oncology, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Celina
authors.initials: C
authors.lastname: Ang
authors.affiliation: Division of Surgical Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: John T
authors.initials: JT
authors.lastname: Miura
authors.affiliation: Division of Surgical Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: T Clark
authors.initials: TC
authors.lastname: Gamblin
authors.affiliation: Department of Medicine, Hematology/Oncology, Georgetown University Medical Center, Washington, DC.
authors.forename: Ruth
authors.initials: R
authors.lastname: He
authors.affiliation: Caris Life Sciences, Phoenix, Arizona.
authors.forename: Joanne
authors.initials: J
authors.lastname: Xiu
authors.affiliation: Caris Life Sciences, Phoenix, Arizona.
authors.forename: Sherri Z
authors.initials: SZ
authors.lastname: Millis
authors.affiliation: Caris Life Sciences, Phoenix, Arizona.
authors.forename: Zoran
authors.initials: Z
authors.lastname: Gatalica
authors.affiliation: Caris Life Sciences, Phoenix, Arizona.
authors.forename: Sandeep K
authors.initials: SK
authors.lastname: Reddy
authors.affiliation: Department of Medicine, Hematology/Oncology, Penn State Hershey Cancer Institute, Hershey, Pennsylvania.
authors.forename: Nelson S
authors.initials: NS
authors.lastname: Yee
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York.|Department of Medicine, Hematology/Oncology, Weill Cornell Medical College, New York, New York.
authors.forename: Ghassan K
authors.initials: GK
authors.lastname: Abou-Alfa
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000032:analysis*; D006528:Carcinoma, Hepatocellular / Q000737:chemistry* / Q000188:drug therapy; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000737:chemistry* / Q000188:drug therapy; D008175:Lung Neoplasms / Q000556:secondary / Q000628:therapy; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009154:Mutation; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives; D010671:Phenylurea Compounds / Q000008:administration & dosage; D000081082:Phosphoinositide-3 Kinase Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D012189:Retrospective Studies; D000077157:Sorafenib; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D051176:beta Catenin / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C495270:CTNNB1 protein, human; D010671:Phenylurea Compounds; D000081082:Phosphoinositide-3 Kinase Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin; D009536:Niacinamide; D000077157:Sorafenib; D000069347:Erlotinib Hydrochloride; D011505:Protein-Tyrosine Kinases
keywords: hepatocellular carcinoma; multiplatform molecular profiling; targeted therapy