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

TitleTSC1/2 mutations define a molecular subset of HCC with aggressive behaviour and treatment implication
Authors
Issue Date2017
PublisherBMJ Publishing Group. The Journal's web site is located at http://gut.bmjjournals.com/
Citation
Gut, 2017, v. 66 n. 8, p. 1496-1506 How to Cite?
AbstractObjective We 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. Design We 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. Results 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 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. Conclusions Taken 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.
Persistent Identifierhttp://hdl.handle.net/10722/237038
ISSN
2017 Impact Factor: 17.016
2015 SCImago Journal Rankings: 6.474
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorHo, DWH-
dc.contributor.authorChan, LK-
dc.contributor.authorChiu, YT-
dc.contributor.authorXU, M-
dc.contributor.authorPoon, RTP-
dc.contributor.authorCheung, TT-
dc.contributor.authorTang, CN-
dc.contributor.authorTang, VWL-
dc.contributor.authorLo, ILO-
dc.contributor.authorLam, PWY-
dc.contributor.authorYau, DTW-
dc.contributor.authorLi, M-
dc.contributor.authorWong, CM-
dc.contributor.authorNg, IOL-
dc.date.accessioned2016-12-20T06:15:19Z-
dc.date.available2016-12-20T06:15:19Z-
dc.date.issued2017-
dc.identifier.citationGut, 2017, v. 66 n. 8, p. 1496-1506-
dc.identifier.issn0017-5749-
dc.identifier.urihttp://hdl.handle.net/10722/237038-
dc.description.abstractObjective We 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. Design We 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. Results 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 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. Conclusions Taken 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.-
dc.languageeng-
dc.publisherBMJ Publishing Group. The Journal's web site is located at http://gut.bmjjournals.com/-
dc.relation.ispartofGut-
dc.rightsGut. Copyright © BMJ Publishing Group.-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.titleTSC1/2 mutations define a molecular subset of HCC with aggressive behaviour and treatment implication-
dc.typeArticle-
dc.identifier.emailHo, DWH: dwhho@hku.hk-
dc.identifier.emailChan, LK: lkchan1@hku.hk-
dc.identifier.emailChiu, YT: ellechiu@pathology.hku.hk-
dc.identifier.emailPoon, RTP: poontp@hku.hk-
dc.identifier.emailCheung, TT: cheung68@hku.hk-
dc.identifier.emailLi, M: mxli@hku.hk-
dc.identifier.emailWong, CM: jackwong@pathology.hku.hk-
dc.identifier.emailNg, IOL: iolng@hku.hk-
dc.identifier.authorityHo, DWH=rp02285-
dc.identifier.authorityChan, LK=rp02289-
dc.identifier.authorityPoon, RTP=rp00446-
dc.identifier.authorityCheung, TT=rp02129-
dc.identifier.authorityLi, M=rp01722-
dc.identifier.authorityWong, CM=rp00231-
dc.identifier.authorityNg, IOL=rp00335-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1136/gutjnl-2016-312734-
dc.identifier.scopuseid_2-s2.0-85006968925-
dc.identifier.hkuros270914-
dc.identifier.volume66-
dc.identifier.issue8-
dc.identifier.spage1496-
dc.identifier.epage1506-
dc.identifier.isiWOS:000405191200020-
dc.publisher.placeUnited Kingdom-

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