PMID- 27974549
OWN - NLM
STAT- MEDLINE
DCOM- 20170905
LR  - 20211204
IS  - 1468-3288 (Electronic)
IS  - 0017-5749 (Print)
IS  - 0017-5749 (Linking)
VI  - 66
IP  - 8
DP  - 2017 Aug
TI  - TSC1/2 mutations define a molecular subset of HCC with aggressive behaviour and 
      treatment implication.
PG  - 1496-1506
LID - 10.1136/gutjnl-2016-312734 [doi]
AB  - OBJECTIVE: 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.
CI  - Published by the BMJ Publishing Group Limited. For permission to use (where not 
      already granted under a licence) please go to 
      http://www.bmj.com/company/products-services/rights-and-licensing/.
FAU - Ho, Daniel W H
AU  - Ho DWH
AUID- ORCID: 0000-0003-3884-296X
AD  - Department of Pathology, The University of Hong Kong, Hong Kong, Hong Kong.
AD  - State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, 
      Hong Kong.
FAU - Chan, Lo K
AU  - Chan LK
AD  - Department of Pathology, The University of Hong Kong, Hong Kong, Hong Kong.
AD  - State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, 
      Hong Kong.
FAU - Chiu, Yung T
AU  - Chiu YT
AD  - Department of Pathology, The University of Hong Kong, Hong Kong, Hong Kong.
AD  - State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, 
      Hong Kong.
FAU - Xu, Iris M J
AU  - Xu IMJ
AD  - Department of Pathology, The University of Hong Kong, Hong Kong, Hong Kong.
AD  - State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, 
      Hong Kong.
FAU - Poon, Ronnie T P
AU  - Poon RTP
AD  - State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, 
      Hong Kong.
AD  - Department of Surgery, The University of Hong Kong, Hong Kong, Hong Kong.
FAU - Cheung, Tan T
AU  - Cheung TT
AD  - Department of Surgery, The University of Hong Kong, Hong Kong, Hong Kong.
FAU - Tang, Chung N
AU  - Tang CN
AD  - Department of Surgery, Pamela Youde Hospital, Hong Kong, Hong Kong.
FAU - Tang, Victor W L
AU  - Tang VWL
AD  - Department of Pathology, Pamela Youde Hospital, Hong Kong, Hong Kong.
FAU - Lo, Irene L O
AU  - Lo ILO
AD  - Department of Surgery, Queen Elizabeth Hospital, Hong Kong, Hong Kong.
FAU - Lam, Polly W Y
AU  - Lam PWY
AD  - Department of Pathology, Queen Elizabeth Hospital, Hong Kong, Hong Kong.
FAU - Yau, Derek T W
AU  - Yau DTW
AD  - Department of Pathology, Queen Elizabeth Hospital, Hong Kong, Hong Kong.
FAU - Li, Miao X
AU  - Li MX
AD  - Department of Psychiatry and Center for Genomics Science, The University of Hong 
      Kong, Hong Kong, Hong Kong.
FAU - Wong, Chun M
AU  - Wong CM
AD  - Department of Pathology, The University of Hong Kong, Hong Kong, Hong Kong.
AD  - State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, 
      Hong Kong.
FAU - Ng, Irene O L
AU  - Ng IOL
AD  - Department of Pathology, The University of Hong Kong, Hong Kong, Hong Kong.
AD  - State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, 
      Hong Kong.
LA  - eng
PT  - Journal Article
DEP - 20161214
PL  - England
TA  - Gut
JT  - Gut
JID - 2985108R
RN  - 0 (ARID1A protein, human)
RN  - 0 (AXIN1 protein, human)
RN  - 0 (Antibiotics, Antineoplastic)
RN  - 0 (Axin Protein)
RN  - 0 (CTNNB1 protein, human)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Nuclear Proteins)
RN  - 0 (TSC1 protein, human)
RN  - 0 (TSC2 protein, human)
RN  - 0 (Transcription Factors)
RN  - 0 (Tsc1 protein, mouse)
RN  - 0 (Tsc2 protein, mouse)
RN  - 0 (Tuberous Sclerosis Complex 1 Protein)
RN  - 0 (Tuberous Sclerosis Complex 2 Protein)
RN  - 0 (Tumor Suppressor Protein p53)
RN  - 0 (Tumor Suppressor Proteins)
RN  - 0 (beta Catenin)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
CIN - Gut. 2017 Aug;66(8):1352-1354. PMID: 28100646
CIN - Gut. 2018 May;67(5):991-993. PMID: 28899984
MH  - Adult
MH  - Aged
MH  - Animals
MH  - Antibiotics, Antineoplastic/pharmacology/*therapeutic use
MH  - Axin Protein/genetics
MH  - Carcinoma, Hepatocellular/chemistry/*genetics/metabolism
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects/genetics
MH  - DNA Mutational Analysis
MH  - DNA-Binding Proteins
MH  - Female
MH  - Humans
MH  - Liver Neoplasms/chemistry/*genetics/metabolism
MH  - Male
MH  - Mice
MH  - Middle Aged
MH  - Mutation Rate
MH  - Neoplasm Transplantation
MH  - Nuclear Proteins/genetics
MH  - Signal Transduction
MH  - Sirolimus/pharmacology/*therapeutic use
MH  - TOR Serine-Threonine Kinases/*metabolism
MH  - Transcription Factors/genetics
MH  - Tuberous Sclerosis Complex 1 Protein
MH  - Tuberous Sclerosis Complex 2 Protein
MH  - Tumor Stem Cell Assay
MH  - Tumor Suppressor Protein p53/genetics
MH  - Tumor Suppressor Proteins/analysis/*genetics
MH  - Young Adult
MH  - beta Catenin/genetics
PMC - PMC5530480
OTO - NOTNLM
OT  - GENE MUTATION
OT  - HEPATITIS B
OT  - HEPATOCELLULAR CARCINOMA
OT  - MUTATION SCREENING
COIS- Competing interests: None declared.
EDAT- 2016/12/16 06:00
MHDA- 2017/09/07 06:00
PMCR- 2017/07/27
CRDT- 2016/12/16 06:00
PHST- 2016/07/26 00:00 [received]
PHST- 2016/11/07 00:00 [revised]
PHST- 2016/11/23 00:00 [accepted]
PHST- 2016/12/16 06:00 [pubmed]
PHST- 2017/09/07 06:00 [medline]
PHST- 2016/12/16 06:00 [entrez]
PHST- 2017/07/27 00:00 [pmc-release]
AID - gutjnl-2016-312734 [pii]
AID - 10.1136/gutjnl-2016-312734 [doi]
PST - ppublish
SO  - Gut. 2017 Aug;66(8):1496-1506. doi: 10.1136/gutjnl-2016-312734. Epub 2016 Dec 14.