Clinical implication of molecular classifications in HCC

Abstract

Our increasing understanding of HCC biology holds promise for personalized care and in the development of molecular drugs. The identification of new or important molecular targets can be translated into clinical practice. The ultimate goal of precision medicine is to utilize molecular information to assign patients to the most effective treatment. However, the molecular alterations in advanced HCCs are quite diverse. Classifications of different HCC subtypes combining histology and gene mutations have been proposed. These may provide guidance for future consolidation but currently consensus for integrative morphological-molecular classification has not yet reached. In this presentation, recent data will be discussed to demonstrate how genomic/genetic analysis of patients’ HCC samples can help identify important molecular targets and possibly molecular signature of HCC for personalized treatment. We investigated the mutational landscape of mammalian target of rapamycin (mTOR) signaling cascade in HCCs with chronic HBV background, aiming to evaluate and delineate mutation-dependent mechanism of mTOR hyperactivation in hepatocarcinogenesis. Next-generation sequencing was performed on human HCC samples and HCC cell line panel. Systematic mutational screening of mTOR pathway-related genes was undertaken and mutant genes were evaluated based on their recurrence. We identified and confirmed multiple mTOR components as recurrently mutated in HBV-associated HCCs. Of significance, we detected frequent (16.2%, n = 18/111) mutations of TSC1 and TSC2 genes in the HCC samples. The spectrum of TSC1/2 mutations likely disrupts the endogenous gene functions in suppressing the downstream mTOR activity through different mechanisms and leads to more aggressive tumor behaviour. Mutational disruption of TSC1 and TSC2 was also observed in HCC cell lines and our HCC patient-derived tumor xenografts (PDTX) models. TSC-mutant cells exhibited reduced colony-forming ability on rapamycin treatment. With the use of biologically relevant TSC2-mutant PDTXs, we demonstrated the therapeutic benefits of the hypersensitivity towards rapamycin treatment. Our findings suggest the significance of previously undocumented mutation dependent mTOR hyperactivation and frequent TSC1/2 mutations in HBV-associated HCCs. They define a molecular subset of HCC having genetic aberrations in mTOR signalling, with potential significance of effective specific drug therapy. On the other hand, fibrolamellar HCC (FL-HCC) is a subtype of HCC occurring mostly in young patients. A segmental deletion resulting in DNAJB1-PRKACA gene fusion is now recognized as the signature genetic event of FL-HCC. DNAJB1-PRKACA fusion kinase is an oncogenic driver and candidate drug target for FL-HCC. Identification of these specific molecular targets can be useful in novel clinical treatment.