title: Neoangiogenesis-related genes are hallmarks of fast-growing hepatocellular carcinomas and worst survival. Results from a prospective study.
abstract: OBJECTIVE
  The biological heterogeneity of hepatocellular carcinoma (HCC) makes prognosis difficult. We translate the results of a genome-wide high-throughput analysis into a tool that accurately predicts at presentation tumour growth and survival of patients with HCC.
  
  
  METHODS
  Ultrasound surveillance identified HCC in 78 (training set) and 54 (validation set) consecutive patients with cirrhosis. Patients underwent two CT scans 6 weeks apart (no treatment in-between) to determine tumour volumes (V0 and V1) and calculate HCC doubling time. Baseline-paired HCC and surrounding tissue biopsies for microarray study (Agilent Whole Human Genome Oligo Microarrays) were also obtained. Predictors of survival were assessed by multivariate Cox model.
  
  
  RESULTS
  Calculated tumour doubling times ranged from 30 to 621 days (mean, 107±91 days; median, 83 days) and were divided into quartiles: ≤53 days (n=19), 54-82 days (n=20), 83-110 days (n=20) and ≥111 days (n=19). Median survival according to doubling time was significantly lower for the first quartile versus the others (11 vs 41 months, 42, and 47 months, respectively) (p<0.0001). A five-gene transcriptomic hepatic signature including angiopoietin-2 (ANGPT2), delta-like ligand 4 (DLL4), neuropilin (NRP)/tolloid (TLL)-like 2 (NETO2), endothelial cell-specific molecule-1 (ESM1), and nuclear receptor subfamily 4, group A, member 1 (NR4A1) was found to accurately identify rapidly growing HCCs of the first quartile (ROC AUC: 0.961; 95% CI 0.919 to 1.000; p<0.0001) and to be an independent factor for mortality (HR: 3.987; 95% CI 1.941 to 8.193, p<0.0001).
  
  
  CONCLUSIONS
  The hepatic five-gene signature was able to predict HCC growth in individual patient and the consequent risk of death. This implies a role of this molecular tool in the future therapeutic management of patients with HCC.
  
  
  BACKGROUND
  ClinicalTrials.gov Identifier: NCT01657695.
authors: Division of Gastroenterology, AOU Modena, Modena, Italy.
authors: Erica
authors: E
authors: Villa
authors: Division of Gastroenterology, AOU Modena, Modena, Italy.
authors: Rosina
authors: R
authors: Critelli
authors: Division of Gastroenterology, AOU Modena, Modena, Italy.
authors: Barbara
authors: B
authors: Lei
authors: Institute of Radiology, AOU Modena, Modena, Italy.
authors: Guido
authors: G
authors: Marzocchi
authors: Division of Gastroenterology, DiBiMIS, University of Palermo, Palermo, Italy.
authors: Calogero
authors: C
authors: Cammà
authors: Institute of Internal Medicine, University of Bari, Bari, Italy.
authors: Gianluigi
authors: G
authors: Giannelli
authors: Medical Clinic, University of Padua, Padua, Italy.
authors: Patrizia
authors: P
authors: Pontisso
authors: Division of Gastroenterology, DiBiMIS, University of Palermo, Palermo, Italy.
authors: Giuseppe
authors: G
authors: Cabibbo
authors: Dipartimento di Scienze Statistiche e Matematiche 'S. Vianelli', University of Palermo, Palermo, Italy.
authors: Marco
authors: M
authors: Enea
authors: Institute of Radiology, AOU Modena, Modena, Italy.
authors: Stefano
authors: S
authors: Colopi
authors: Institute of Radiology, AOU Modena, Modena, Italy.
authors: Cristian
authors: C
authors: Caporali
authors: Department of Internal Medicine, Clinical and Molecular Hepatology, University of Messina, Messina, Italy.
authors: Teresa
authors: T
authors: Pollicino
authors: Division of Gastroenterology, AOU Modena, Modena, Italy.
authors: Fabiola
authors: F
authors: Milosa
authors: Division of Gastroenterology, AOU Modena, Modena, Italy.
authors: Aimilia
authors: A
authors: Karampatou
authors: Division of Gastroenterology, AOU Modena, Modena, Italy.
authors: Paola
authors: P
authors: Todesca
authors: Division of Gastroenterology, AOU Modena, Modena, Italy.
authors: Elena
authors: E
authors: Bertolini
authors: Department of Pathology, AOU Modena, Modena, Italy.
authors: Livia
authors: L
authors: Maccio
authors: Metabolomic Unit, CicBioGune, Bilbao, Spain.
authors: Maria Luz
authors: ML
authors: Martinez-Chantar
authors: Division of Gastroenterology, AOU Modena, Modena, Italy.
authors: Elena
authors: E
authors: Turola
authors: Division of Gastroenterology, AOU Modena, Modena, Italy.
authors: Mariagrazia
authors: M
authors: Del Buono
authors: Division of Gastroenterology, AOU Modena, Modena, Italy.
authors: Nicola
authors: N
authors: De Maria
authors: Medicina Metabolica, Nuovo Ospedale S. Agostino, Modena, Italy.
authors: Stefano
authors: S
authors: Ballestri
authors: Division of Gastroenterology, AOU Modena, Modena, Italy.
authors: Filippo
authors: F
authors: Schepis
authors: Medicina Metabolica, Nuovo Ospedale S. Agostino, Modena, Italy.
authors: Paola
authors: P
authors: Loria
authors: Department of Surgery, AOU Modena, Modena, Italy.
authors: Giorgio
authors: G
authors: Enrico Gerunda
authors: Department of Pathology, AOU Modena, Modena, Italy.
authors: Luisa
authors: L
authors: Losi
authors: Liver Transplant, University of Padua, Padua, Italy.
authors: Umberto
authors: U
authors: Cillo
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D018450:Disease Progression; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000235:genetics; D011446:Prospective Studies; D015996:Survival Rate; D013997:Time Factors; D047368:Tumor Burden
keywords: HEPATOCELLULAR CARCINOMA; LIVER IMAGING; MOLECULAR CARCINOGENESIS; MOLECULAR ONCOLOGY