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Gut. 2016 May;65(5):861-9. doi: 10.1136/gutjnl-2014-308483. Epub 2015 Feb 9.

Neoangiogenesis-related genes are hallmarks of fast-growing hepatocellular carcinomas and worst survival. Results from a prospective study.

Author information

1
Division of Gastroenterology, AOU Modena, Modena, Italy.
2
Institute of Radiology, AOU Modena, Modena, Italy.
3
Division of Gastroenterology, DiBiMIS, University of Palermo, Palermo, Italy.
4
Institute of Internal Medicine, University of Bari, Bari, Italy.
5
Medical Clinic, University of Padua, Padua, Italy.
6
Dipartimento di Scienze Statistiche e Matematiche 'S. Vianelli', University of Palermo, Palermo, Italy.
7
Department of Internal Medicine, Clinical and Molecular Hepatology, University of Messina, Messina, Italy.
8
Department of Pathology, AOU Modena, Modena, Italy.
9
Metabolomic Unit, CicBioGune, Bilbao, Spain.
10
Medicina Metabolica, Nuovo Ospedale S. Agostino, Modena, Italy.
11
Department of Surgery, AOU Modena, Modena, Italy.
12
Liver Transplant, University of Padua, Padua, Italy.

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.

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:

ClinicalTrials.gov Identifier: NCT01657695.

KEYWORDS:

HEPATOCELLULAR CARCINOMA; LIVER IMAGING; MOLECULAR CARCINOGENESIS; MOLECULAR ONCOLOGY

PMID:
25666192
DOI:
10.1136/gutjnl-2014-308483
[Indexed for MEDLINE]

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