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TSC1/2 Mutations Define a Molecular Subset of HCC with Aggressive

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TSC1/2 Mutations Define a Molecular Subset of HCC with Aggressive Hepatology ORIGINAL ARTICLE TSC1/2 mutations define a molecular subset of HCC Gut: first published as 10.1136/gutjnl-2016-312734 on 14 December 2016. Downloaded from with aggressive behaviour and treatment implication Daniel W H Ho,1,2 Lo K Chan,1,2 Yung T Chiu,1,2 Iris M J Xu,1,2 Ronnie T P Poon,2,3 Tan T Cheung,3 Chung N Tang,4 Victor W L Tang,5 Irene L O Lo,6 Polly W Y Lam,7 Derek T W Yau,7 Miao X Li,8 Chun M Wong,1,2 Irene O L Ng1,2 ► Additional material is ABSTRACT published online only. To view Objective We investigated the mutational landscape of Significance of this study please visit the journal online (http:// dx. doi. org/ 10. 1136/ mammalian target of rapamycin (mTOR) signalling gutjnl- 2016- 312734). cascade in hepatocellular carcinomas (HCCs) with chronic HBV background, aiming to evaluate and What is already known on this subject? For numbered affiliations see ▸ end of article. delineate mutation-dependent mechanism of mTOR Hepatocellular carcinoma (HCC) is a common hyperactivation in hepatocarcinogenesis. cancer and leading cause of death worldwide. ▸ Correspondence to Design We performed next-generation sequencing on HCC is heterogeneous with various risk factors Professor Irene Oi-Lin Ng or Dr human HCC samples and cell line panel. Systematic including viral infection (HBV and HCV), Chun-Ming Wong, Department mutational screening of mTOR pathway-related genes alcoholism and exposure to aflatoxin B1. of Pathology, University was undertaken and mutant genes were evaluated ▸ Activation of mammalian target of rapamycin Pathology Building, Queen Mary (mTOR) signalling cascade is resulted from Hospital, Pokfulam, Hong Kong; based on their recurrence. Protein expressions of iolng@ hkucc. hku. hk or tuberous sclerosis complex (TSC)1, TSC2 and pRPS6 ligand-dependent signals from epidermal growth jackwong@ pathology. hku. hk were assessed by immunohistochemistry in human HCC factor and insulin-like growth factor signalling. samples. Rapamycin sensitivity was estimated by colony- What are the new findings? DWHH and LKC contributed formation assay in HCC cell lines and the treatment was equally. ▸ There are frequent mutational disruptions on further tested using our patient-derived tumour xenograft multiple key and canonical components of mTOR Received 26 July 2016 (PDTX) models. signalling cascade. fi fi Revised 7 November 2016 Results We identi ed and con rmed multiple mTOR ▸ Mutation-dependent mechanism is likely to be Accepted 23 November 2016 components as recurrently mutated in HBV-associated another major cause leading to mTOR Published Online First fi 14 December 2016 HCCs. Of signi cance, we detected frequent (16.2%, hyperactivation. n=18/111) mutations of TSC1 and TSC2 genes in the ▸ Tuberous sclerosis complex (TSC)1 and TSC2 are HCC samples. The spectrum of TSC1/2 mutations likely the most frequently mutated mTOR pathway- disrupts the endogenous gene functions in suppressing related genes and they collectively define a novel http://gut.bmj.com/ the downstream mTOR activity through different molecular subset of human HCCs with more mechanisms and leads to more aggressive tumour aggressive tumour behaviours. behaviour. Mutational disruption of TSC1 and TSC2 was ▸ Our study signifies personalised therapeutic option also observed in HCC cell lines and our PDTX models. for a novel molecular subset of patients with TSC-mutant cells exhibited reduced colony-forming ability susceptible mutant HCC through the inhibition of on rapamycin treatment. With the use of biologically mTOR signalling. relevant TSC2-mutant PDTXs, we demonstrated the on October 2, 2021 by guest. Protected copyright. How might it impact on clinical practice in therapeutic benefits of the hypersensitivity towards the foreseeable future? rapamycin treatment. ▸ TSC1/2 mutations represent one of the most Conclusions Taken together, our findings suggest the fi frequent single categories of genetic alterations signi cance of previously undocumented mutation- found in human HCC and mTOR signalling dependent mTOR hyperactivation and frequent TSC1/2 cascade represents one of the most prominent fi mutations in HBV-associated HCCs. They de ne a therapeutic targets in HCC. molecular subset of HCC having genetic aberrations in ▸ There is frequent mutation-dependent mTOR mTOR signalling, with potential significance of effective hyperactivation, which defines a novel molecular specific drug therapy. subset of human HCC and is likely to be actionable through inhibition by rapamycin or its derivatives. ▸ ► http:// dx. doi. org/ 10. 1136/ Through perfect combination of both high- gutjnl- 2016- 313462 throughput next-generation sequencing-based INTRODUCTION mutation screening and patient-derived tumour Liver cancer (hepatocellular carcinoma (HCC)) is a xenograft model, our study demonstrates, with major malignancy worldwide and the second most necessary supportive evidence correlating common fatal cancer in China, including Hong mutational findings and drug testing, the Kong and Southeast Asia. About 55% of all new potential personalised treatment on relevant 12 To cite: Ho DWH, cases worldwide occur in China. Chronic HBV patients with HCC carrying specific molecular Chan LK, Chiu YT, et al. Gut infection is the major underlying risk factor. HCC alterations. 2017;66:1496–1506. is deadly because of high recurrence rate even after 1496 Ho DWH, et al. Gut 2017;66:1496–1506. doi:10.1136/gutjnl-2016-312734 Hepatology surgical resection and frequent metastasis. Unfortunately, the cell population of tissues. Use of human samples was approved overall response rate of patients with HCC to chemotherapy is by the institutional review board of the University of Hong Gut: first published as 10.1136/gutjnl-2016-312734 on 14 December 2016. Downloaded from unsatisfactory due to the highly chemoresistant nature of the Kong/Hospital Authority Hong Kong West Cluster (see online tumour and the toxicity of the chemotherapeutic agents. On the supplementary materials and methods for the detailed method- other hand, Sorafenib, a multiple tyrosine-kinase inhibitor and ology regarding NGS-based mutation evaluation, subsequent the only Food and Drug Administration-approved molecularly data validation and functional characterisation). targeted drug for HCC, has demonstrated only a modest sur- vival benefit in patients with HCC, with the median survival RESULTS only 2–3 months longer than the placebo arm in large-scale Targeted-seq revealed recurrently mutated genes in mTOR trials in both Caucasians and Asians.34There is an urgent need pathway in HCC to identify strategic molecular targets for developing new and To explore the pattern and importance of genetic alterations in effective molecularly targeted therapy. In this regard, investiga- mTOR pathway genes, we performed deep-targeted-seq in a tion of the mutational landscape of HCC by next-generation large cohort of 95 human HCC tumour samples (targeted-seq sequencing (NGS) for novel, recurrently mutated targets with cohort) for 81 mTOR pathway-related genes (see online therapeutic implication would be valuable and would help in supplementary table S2) selected based on Kyoto Encyclopedia rational designing of personalised treatment strategy for patients of Genes and Genomes pathway definition and literature search, with HCC. with mean depth of base coverage of 154.3× (range: Recent studies have demonstrated phosphoinositide 3-kinase 135.9–197.1) (see online supplementary table S3). Normal (PI3K)/protein kinase B (PKB/AKT)/mammalian target of rapamy- polymorphic sequence variants were removed by background fil- cin (mTOR) signalling pathway to have pivotal role in cancers, tering against reported variants deposited in public repositories. including HCC.56Components of mTOR signalling pathway are Of the 95 human HCC tumours studied, 69 (73%) carried at frequently upregulated in human HCCs.7 Activation of mTOR least one mutation in our selected mTOR-related gene set. signalling cascade was believed to be the result of ligand- Among the 81 genes, 25 (31%) were found to be recurrently dependent signals from epidermal growth factor and insulin-like mutated (figure 1A, upper part), while 22 (27%) were singleton growth factor signalling, rather than from a mutation-dependent (figure 1A, lower part). The remaining 34 genes (42%) showed mechanism.6 In accordance, reported literature has revealed low no mutations in this cohort. All the mutant genes were sorted frequency of mutations in mTOR signalling pathway.7 and tabulated according to their frequency of occurrence (figure To systematically exploit the mutational landscape of mTOR 1A) and displayed in a pathway diagram to illustrate their poten- signalling cascade in chronic HBV background, we performed tial roles in the mTOR signalling (figure 1B). In order to iden- deep NGS-based targeted DNA sequencing (targeted-seq) on tify the potential key signalling components frequently mutated a panel of 81 selected mTOR pathway-related genes using a large in HCC, we paid particular attention to the top-ranking mutant cohort of 95 HBV-associated HCC cases. This initial observation genes. We found that six genes (and the corresponding pro- was further augmented by mutational screening using whole- teins), namely TSC2 (TSC2), HIF1A (HIF1α), PABPC3 exome sequencing (WES) on 16 additional HBV-associated HCC (PABPC3), RB1CC1 (ATG17), RPS6KA3 (RSK2) and TSC1 cases, as well as whole-transcriptome sequencing (WTS) and (TSC1), were frequently affected in more than 5% of the cases Sanger sequencing in a panel of HCC cell lines. We
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