Elsevier

Journal of Hepatology

Volume 55, Issue 6, December 2011, Pages 1325-1331
Journal of Hepatology

Research Article
Gene-expression signature of vascular invasion in hepatocellular carcinoma

https://doi.org/10.1016/j.jhep.2011.02.034Get rights and content

Background & Aims

Vascular invasion is a major predictor of tumor recurrence after surgical treatments for hepatocellular carcinoma (HCC). While macroscopic vascular invasion can be detected by radiological techniques, pre-operative detection of microscopic vascular invasion, which complicates 30–40% of patients with early tumors, remains elusive.

Methods

A total of 214 patients with hepatocellular carcinoma who underwent resection were included in the study. By using genome-wide gene-expression profiling of 79 hepatitis C-related hepatocellular carcinoma samples (training set), a gene-expression signature associated with vascular invasion was defined. The signature was validated in formalin-fixed paraffin-embedded tissues obtained from an independent set of 135 patients with various etiologies.

Results

A 35-gene signature of vascular invasion was defined in the training set, predicting vascular invasion with an accuracy of 69%. The signature was independently associated with the presence of vascular invasion (OR 3.38, 95% CI 1.48–7.71, p = 0.003) along with tumor size (diameter greater than 3 cm, OR 2.66, 95% CI 1.17–6.05, p = 0.02). In the validation set, the signature discarded the presence of vascular invasion with a negative predictive value of 0.77, and significantly improved the diagnostic power of tumor size alone (p = 0.045).

Conclusions

The assessment of a gene-expression signature obtained from resected biopsied tumor specimens improved the diagnosis of vascular invasion beyond clinical variable-based prediction. The signature may aid in candidate selection for liver transplantation, and guide the design of clinical trials with experimental adjuvant therapies.

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

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