Prognostic Gene Expression Signature for Patients With Hepatitis C–Related Early-Stage Cirrhosis

Abstract

Background & Aims Liver cirrhosis affects 1%–2% of population and is the major risk factor of hepatocellular carcinoma (HCC). Hepatitis C cirrhosis-related HCC is the most rapidly increasing cause of cancer death in the US. Non-invasive methods have been developed to identify patients with asymptomatic, early-stage cirrhosis, increasing the burden of HCC surveillance, but biomarkers are needed to identify patients with cirrhosis who are most in need of surveillance. We investigated whether a liver-derived 186-gene signature previously associated with outcomes of patients with HCC is prognostic for patients newly diagnosed with cirrhosis but without HCC. Methods We performed gene expression profile analysis of formalin-fixed needle biopsies from the livers of 216 patients with hepatitis C-related early-stage (Child-Pugh class A) cirrhosis who were prospectively followed for a median of 10 years at an Italian center. We evaluated whether the 186-gene signature was associated with death, progression of cirrhosis, and development of HCC. Results Fifty-five (25%), 101 (47%), and 60 (28%) patients were classified as having poor-, intermediate-, and good-prognosis signatures, respectively. In multivariable Cox regression modeling, the poor-prognosis signature was significantly associated with death (P=.004), progression to advanced cirrhosis (P<.001), and development of HCC (P=.009). The 10-year rates of survival were 63%, 74%, and 85% and the annual incidences of HCC were 5.8%, 2.2%, and 1.5% for patients with poor-, intermediate-, and good-prognosis signatures, respectively. Conclusions A 186-gene signature used to predict outcomes of patients with HCC is also associated with outcomes of patients with hepatitis C-related early-stage cirrhosis. This signature might be used to identify patients with cirrhosis in most need of surveillance and strategies to prevent their development of HCC.

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“…The prognostic 35‐gene signature was implemented in the digital transcript counting (nCounter) assay (NanoString) 19. Total RNA (200–400 ng) was assayed according to the manufacturer's instructions.…”

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“…Gene signatures associated with tumor liver tissues allowed the prediction of early recurrence [9,18] and patient survival [7] after surgery. Interestingly, some studies reported gene expression signatures associated with the non-tumor adjacent liver tissue that provide an additional value in prognosis prediction [19,20,21,22] (table 2). …”

“…Microarray technology has been also used to study gene expression to predict HCC outcome in non-tumor liver tissue, usually affected by chronic hepatitis or cirrhosis, [19,20,21,22]. In 2008, Hoshida et al [19 ]reported a 186-gene signature from liver tissue adjacent to the tumor that predicted survival after surgery for HCC and also predicted the outcome of liver cirrhosis.…”

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“…In this regard, several genetic expression profiles with prognostic significance have been suggested (51)(52)(53)(54)(55)(56)(57). However, to date, it has not been shown that the presence of a specific molecular pattern allows a concrete therapeutic decision.…”