Primary liver cancer genome sequencing: translational implications and challenges.

Ziogas DE1,2, Kyrochristos ID1,3, Glantzounis GK3, Christodoulou D4, Felekouras E5, Roukos DH1,3,6.

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Abstract

INTRODUCTION:

The prognosis of primary liver cancer (PLC) remains poor and is explained by the slow progress in understanding the molecular pathways driving tumorigenesis, therapeutic resistance and relapse. For early PLCs, complete surgical resection is the only effective treatment, with sorafenib and, more recently, regorafenib prolonging overall survival by a few months. Areas covered: Application of next-generation sequencing (NGS), including targeted NGS (tNGS), whole-exome sequencing (WES), whole-genome sequencing (WGS) and RNA sequencing (RNAseq), on clinical samples from patients with hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) could aid in comprehending tumorigenesis, genetic and genomic heterogeneity, as well as developing molecular classifications for specialized targeted therapy. Expert commentary: Despite the many overenthusiastic original and opinion reports, we have critically reviewed available NGS studies, with focus on the challenges to achieve clinical implications. Based on the recommendations for valid identification of clinically crucial genomic alterations (GAs) by NGS, we propose NGS integration into appropriately designed clinical trials. Furthermore, valid detection of genomic heterogeneity enables the conduction of clinical trials investigating the efficacy both of GAs as prognostic and predictive tools, as well as the discovery of novel oncotargets, on the basis of an early drug development strategy.

KEYWORDS:

Next-generation sequencing; WES; WGS; cancer genome; drugs; hepatocellular cancer; intrahepatic cholangiocarcinoma; novel oncotargets; umbrella and basket studies