Clinical significance of APOB inactivation in hepatocellular carcinoma

Gena Lee,Yeong-Eun Sim,Ju-Seog Lee,Jiwon Koh,Yun Seong Jeong,Sun Young Yim,Eun Wook Joo,Min Jun Kwak,Susie Kah,Do Won Kim

doi:10.1038/s12276-018-0174-2

Abstract

Recent findings from The Cancer Genome Atlas project have provided a comprehensive map of genomic alterations that occur in hepatocellular carcinoma (HCC), including unexpected mutations in apolipoprotein B (APOB). We aimed to determine the clinical significance of this non-oncogenetic mutation in HCC. An Apob gene signature was derived from genes that differed between control mice and mice treated with siRNA specific for Apob (1.5-fold difference; P < 0.005). Human gene expression data were collected from four independent HCC cohorts (n = 941). A prediction model was constructed using Bayesian compound covariate prediction, and the robustness of the APOB gene signature was validated in HCC cohorts. The correlation of the APOB signature with previously validated gene signatures was performed, and network analysis was conducted using ingenuity pathway analysis. APOB inactivation was associated with poor prognosis when the APOB gene signature was applied in all human HCC cohorts. Poor prognosis with APOB inactivation was consistently observed through cross-validation with previously reported gene signatures (NCIP A, HS, high-recurrence SNUR, and high RS subtypes). Knowledge-based gene network analysis using genes that differed between low-APOB and high-APOB groups in all four cohorts revealed that low-APOB activity was associated with upregulation of oncogenic and metastatic regulators, such as HGF, MTIF, ERBB2, FOXM1, and CD44, and inhibition of tumor suppressors, such as TP53 and PTEN. In conclusion, APOB inactivation is associated with poor outcome in patients with HCC, and APOB may play a role in regulating multiple genes involved in HCC development.

Highlights

Liver cancer is the seventh most common cancer globally[1,2], and hepatocellular carcinoma (HCC) represents 75% of cases of primary liver cancer[3]
To identify genes whose expression is associated with Apob expression in mouse liver, we applied a two-sample t-test to gene expression data from mouse livers treated with two Apobspecific siRNAs for Apob expression silencing and control livers from mice treated with phosphate-buffered saline
We refer to the gene expression signature associated with Apob silencing as the “Apob silencing signature (ASS).”

Summary

Introduction

Liver cancer is the seventh most common cancer globally[1,2], and hepatocellular carcinoma (HCC) represents 75% of cases of primary liver cancer[3]. The incidence of liver cancer has increased in the United States over the past 25 years (40,710 estimated new cases in 2017)[4]. Incidence and mortality rates for liver cancer are expected to double over the 10–20 years[5,6]. HCC is the second most lethal cancer type, and the 5-year overall survival rates in the United States are only approximately 11%7. Sorafenib and regorafenib are approved molecular targeted therapies for HCC, they have shown only limited clinical benefit[8,9]. Lack of molecular classification and clinical heterogeneity in HCC are likely the reasons for underdevelopment of standardized treatment for this malignant disease

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