TSC1/2mutations define a molecular subset of HCC with aggressive behaviour and treatment implication

Abstract

ObjectiveWe investigated the mutational landscape of mammalian target of rapamycin (mTOR) signalling cascade in hepatocellular carcinomas (HCCs) with chronic HBV background, aiming to evaluate and delineate mutation-dependent mechanism of mTOR hyperactivation in hepatocarcinogenesis.DesignWe performed next-generation sequencing on human HCC samples and cell line panel. Systematic mutational screening of mTOR pathway-related genes was undertaken and mutant genes were evaluated based on their recurrence. Protein expressions of tuberous sclerosis complex (TSC)1, TSC2 and pRPS6 were assessed by immunohistochemistry in human HCC samples. Rapamycin sensitivity was estimated by colony-formation assay in HCC cell lines and the treatment was further tested using our patient-derived tumour xenograft (PDTX) models.ResultsWe 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 tumour behaviour. Mutational disruption of TSC1 and TSC2 was also observed in HCC cell lines and our 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.ConclusionsTaken together, 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.

Dual Roles of Mammalian Target of Rapamycin in Regulating Liver Injury and Tumorigenesis in Autophagy‐Defective Mouse Liver

“…In response to nutrients and growth factors, mTORC1 is activated and responsible for the increased synthesis of macromolecules and building blocks that are required for cell growth and proliferation . More than 50% of human cancers, including HCC, have aberrant mTORC1 activation, which can mostly be attributed to the loss of function mutations of phosphatase and tensin homolog (PTEN) or tuberous sclerosis complex 1 (TSC1) or TSC2 . Therefore, liver‐specific ablation of PTEN or TSC1 in mice leads to chronic activation of mTORC1, hepatomegaly, and spontaneous liver tumorigenesis .…”

Non-invasive diagnosis of hepatocellular carcinoma revisited

“…We read with interest the recent work by Ho et al demonstrating mutational hyperactivation of mammalian target of rapamycin signalling in a subgroup of hepatocellular carcinoma (HCC) 1. As Berasain and Lechel concluded that the prospect of a positive therapeutic response may outweigh the risk associated with the HCC biopsy procedure2 and histology is essential for confirming a diagnosis of intrahepatic cholangiocarcinoma (ICC),3 we revisited the performance of non-invasive HCC diagnosis as recommended by current guidelines (eg, American Association for the Study of Liver Diseases (AASLD)) in clinical practice 4…”

Targeting the correct target in HCC

“…In Gut , the study of Ho et al 8 used next generation sequencing (NGS)-based targeted DNA sequencing to screen for mutations of mechanistic target of rapamycin (mTOR) pathway-related genes in HBV-associated HCCs. Within a panel of 81 mTOR pathway-related genes, they found the tuberous sclerosis complexes 1 and 2 (TSC1/TSC2) as the most frequently mutated (5.4% and 11.7%).…”

“…The study of Ho et al 8 shows that mutations in the TSC1/2 gene result in the abolition of mTORC1 activity leading to the hyperactivation of mTOR signalling. Their experiments in TSC mutated cell lines as well as in patient-derived tumour xenografts with TSC mutations demonstrate an increased sensitivity to rapamycin treatment 8.…”

“…Their experiments in TSC mutated cell lines as well as in patient-derived tumour xenografts with TSC mutations demonstrate an increased sensitivity to rapamycin treatment 8. mTOR inhibitors have been already tested in clinical trials with sorafenib-refractory or intolerant patients with HCC without significant results.…”