Research ArticleGene-expression signature of vascular invasion in hepatocellular carcinoma
Introduction
Hepatocellular carcinoma is a major global health problem representing the third cause of cancer-related mortality and the most common cause of death among cirrhotic patients [1]. Resection and liver transplantation are considered as the first-line therapeutic options able to potentially cure the disease [2]. However, resection is hampered by a recurrence rate of 70% at 5 years, while relapses complicate liver transplantation in 10–20% of cases. It is known that micro- and macrovascular invasion of the tumor is a major predictive factor of recurrence due to tumor cell dissemination and poor survival [3], [4], [5], [6], [7]. While preoperative imaging techniques are feasible to diagnose macroscopic vascular invasion, documenting microscopic invasion is still challenging, as it is detected only at pathological examination of surgically resected specimen.
Liver transplantation currently offers acceptable long-term survival rates (70% at 5 years) in well-selected hepatocellular carcinoma patients with the use of widely accepted Milan criteria, which are based on the number and size of tumors [8]. Recent studies have suggested that the criteria could be expanded in patients without vascular invasion to achieve a similar survival benefit [4], [9], [10]. Previous efforts have estimated the presence of vascular invasion without relying on postoperative pathological examination by utilizing clinical and/or molecular information [6], [11], [12], [13], [14]. However, validation of these predictors is still lacking.
In the current study, we have developed a 35-gene signature that predicts the presence of vascular invasion in patients with surgically treated hepatocellular carcinoma. The signature is shown to be more sensitive in detecting vascular invasion than previously reported predictors.
Section snippets
Patients and samples
We analyzed a total of 214 hepatocellular carcinoma samples from patients consecutively treated with surgical resection between 1995 and 2006 in three centers integrating the HCC Genomic Consortium: Mount Sinai School of Medicine (New York), Hospital Clínic (Barcelona), and Istituto Nazionale dei Tumori (Milan). Seventy-nine fresh frozen samples (New York, n = 29; Barcelona, n = 24; Milan, n = 26), were used to define the signature (training set) (Fig. 1). All samples were obtained after acquisition
Patient characteristics
Table 1 summarizes clinical characteristics of the patients analyzed in the study. The training set includes mostly Caucasian patients; whereas the validation set comprise a larger number of Asian patients (20%). By study design, all patients in the training set were hepatitis C-related in contrast to the validation set which included tumors of different etiologies, with one-third of patients infected with hepatitis B virus. Tumor characteristics were similar in both cohorts, although tumors in
Discussion
The therapeutic field of hepatocellular carcinoma has changed considerably during the last decade. Outcomes after curative therapies (surgical resection, liver transplantation and local ablation) have improved due to better selection of candidates and surgical techniques [28]. Transcatheter arterial chemoembolization enhances survival in patients with tumors limited to the liver [29], whereas the multikinase inhibitor sorafenib has demonstrated survival benefits for patients with advanced
Conflict of interest
The Authors who have taken part in this study do not have a relationship with the manufacturers of the drugs involved either in the past or present and did not receive funding from the manufacturers to carry out their research.
Financial support
Beatriz Mínguez was the recipient of a grant from Programa de Estancias de Movilidad Postdoctoral en el Extranjero incluidas las ayudas MICINN/Fulbright (EX 2008-0632), Augusto Villanueva was supported by a Sheila Sherlock Fellowship, Sara Toffanin and Vincenzo Mazzaferro were supported by Italian National Ministry of Health and the Italian Association of Cancer Research. Anja Lachenmayer was supported by a postdoctoral fellowship from German Research Foundation. BCLC was supported by the
References (40)
- et al.
Hepatocellular carcinoma
Lancet
(2003) - et al.
Predicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria: a retrospective, exploratory analysis
Lancet Oncol
(2009) - et al.
Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy
J Hepatol
(2003) - et al.
Vascular invasion and histopathologic grading determine outcome after liver transplantation for hepatocellular carcinoma in cirrhosis
Hepatology
(2001) - et al.
A system of classifying microvascular invasion to predict outcome after resection in patients with hepatocellular carcinoma
Gastroenterology
(2009) - et al.
Liver transplantation for hepatocellular carcinoma: comparison of the proposed UCSF criteria with the Milan criteria and the Pittsburgh modified TNM criteria
Liver Transpl
(2002) - et al.
A system of classifying microvascular invasion to predict outcome after resection in patients with hepatocellular carcinoma
Gastroenterology
(2009 Sep) - et al.
A molecular signature to discriminate dysplastic nodules from early hepatocellular carcinoma in HCV cirrhosis
Gastroenterology
(2006) CD24 and human carcinoma: tumor biological aspects
Biomed Pharmacother
(2005)- et al.
CD24 is a new oncogene, early at the multistep process of colorectal cancer carcinogenesis
Gastroenterology
(2006)
Major achievements in hepatocellular carcinoma
Lancet
Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival
Hepatology
Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival
Hepatology
Oligonucleotide microarray for prediction of early intrahepatic recurrence of hepatocellular carcinoma after curative resection
Lancet
Molecular-based prediction of early recurrence in hepatocellular carcinoma
J Hepatol
Design and endpoints of clinical trials in hepatocellular carcinoma
J Natl Cancer Inst
Resection and liver transplantation for hepatocellular carcinoma
Semin Liver Dis
Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis
N Engl J Med
Long-term results with multimodal adjuvant therapy and liver transplantation for the treatment of hepatocellular carcinomas larger than 5 centimeters
Ann Surg
Tumor size predicts vascular invasion and histologic grade: Implications for selection of surgical treatment for hepatocellular carcinoma
Liver Transpl
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