Article Text

Download PDFPDF
Original article
Neoangiogenesis-related genes are hallmarks of fast-growing hepatocellular carcinomas and worst survival. Results from a prospective study
  1. Erica Villa1,
  2. Rosina Critelli1,
  3. Barbara Lei1,
  4. Guido Marzocchi2,
  5. Calogero Cammà3,
  6. Gianluigi Giannelli4,
  7. Patrizia Pontisso5,
  8. Giuseppe Cabibbo3,
  9. Marco Enea6,
  10. Stefano Colopi2,
  11. Cristian Caporali2,
  12. Teresa Pollicino7,
  13. Fabiola Milosa1,
  14. Aimilia Karampatou1,
  15. Paola Todesca1,
  16. Elena Bertolini1,
  17. Livia Maccio8,
  18. Maria Luz Martinez-Chantar9,
  19. Elena Turola1,
  20. Mariagrazia Del Buono1,
  21. Nicola De Maria1,
  22. Stefano Ballestri10,
  23. Filippo Schepis1,
  24. Paola Loria10,
  25. Giorgio Enrico Gerunda11,
  26. Luisa Losi8,
  27. Umberto Cillo12
  1. 1Division of Gastroenterology, AOU Modena, Modena, Italy
  2. 2Institute of Radiology, AOU Modena, Modena, Italy
  3. 3Division of Gastroenterology, DiBiMIS, University of Palermo, Palermo, Italy
  4. 4Institute of Internal Medicine, University of Bari, Bari, Italy
  5. 5Medical Clinic, University of Padua, Padua, Italy
  6. 6Dipartimento di Scienze Statistiche e Matematiche ‘S. Vianelli’, University of Palermo, Palermo, Italy
  7. 7Department of Internal Medicine, Clinical and Molecular Hepatology, University of Messina, Messina, Italy
  8. 8Department of Pathology, AOU Modena, Modena, Italy
  9. 9Metabolomic Unit, CicBioGune, Bilbao, Spain
  10. 10Medicina Metabolica, Nuovo Ospedale S. Agostino, Modena, Italy
  11. 11Department of Surgery, AOU Modena, Modena, Italy
  12. 12Liver Transplant, University of Padua, Padua, Italy
  1. Correspondence to Professor Erica Villa, Department of Internal Medicine, Gastroenterology Unit, Università degli Studi di Modena & Reggio Emilia, and Azienda Ospedaliero-Universitaria di Modena, Via del Pozzo 71, Modena 41124, Italy; erica.villa{at}


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.

Design 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.

Trial registration number Identifier: NCT01657695.


Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.