Josep M Llovet MD PhD Professor of Medicine Director Liver Cancer Program ISM at Mount Sinai NYC Professor of ResearchICREA Head Translational research in hepatic oncology Liver Unit Hospital ID: 916834
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Slide1
Molecular characterization of NASH-HCC
Josep M
Llovet,
MD, PhD
Professor of Medicine. Director, Liver Cancer Program. ISM at Mount Sinai, NYC
Professor of Research-ICREA. Head, Translational research in hepatic oncology. Liver Unit. Hospital Clínic Barcelona.
Slide2Molecular characterization of NASH-HCC
Epidemiology Molecular pathogenesis: from NAFLD to HCC
3. Molecular characterization of NASH-HCC a) Molecular subclasses and pathways
b) Are there unique drivers? c) Specific genotoxicity or cancer field effect?
Slide3Incidence and
mortality of HCC
Villanueva A, NEJM 2019
Epidemiology of liver Cancer
Liver cancer is the sixth most common cancer globally and the fourth leading cause of cancer-related mortality.
Over 850,000 new cases of liver cancer (2018), around 1M (2025)
Eastern Asia: 570,000
Europe: 68,000
United States: 32,000
Liver cancer is the leading cause of death in cirrhotic patients
The incidence of HCC is increasing globally
IARC,
https://gco.iarc.fr/today/home
WHO,
http://www.who.int/healthinfo/global_burden_disease/projections/en/
Slide4Incidence of HCC
Incidence rates of HCC according to geographical area.
Llovet JM et al. Nat Rev Dis Primers 2016
Slide5Incidence and
risk factors-
HCC
Incidence rates of HCC according to geographical area.
Llovet JM et al. Nat Rev Dis Primers 2016
2016: 850K cases
2025: >1M cases
NASH
HCV
Alcoho
l
HBV
AB1
Slide6Global NAFLD prevalence
Younossi
Z et al,
Nat
Rev Gastroenterol Hepatol, 2018
Summary
:
Global
prevalence of NAFLD: 25% of global population
(highest
Middle
East)
Estimated
NAFLD
population
in
the
US
by
2030: 100
million
PNPLA3
SNPs
is
more
prevalent
in
Hispanics
Slide7Risk of HCC in NAFLD
Kanwal
F et al,
Gastroenterology
2018
Summary: Risk of HCC: HR: 7.6 NAFLD vs controls (
Highest
risk: NASH-
Cirrhosis in hispanics
) 20% of NAFLD-HCC are non
cirrhotics
Slide8Risk of HCC in NAFLD
D’Avola
D et al,
Clin
Liv
Dis 2016NASH-HCC with cirrhosis
: 70-80%
NASH-HCC without
cirrhosis
: 20-30%
Slide9Molecular characterization of NASH-HCC
Epidemiology Molecular pathogenesis: from NAFLD to HCC
3. Molecular characterization of NASH-HCC a) Molecular subclasses and pathways
b) Are there unique drivers? c) Specific genotoxicity or cancer field effect?
Slide10Molecular pathogenesis
Anstee
Q, Nat Rev Gastro &
Hepatol
2019
Hepatic substrate overload
Chronic inflammation
Oxidative stress
Chronic liver damage
From NAFLD to HCC
Slide11Molecular pathogenesis
Anstee
Q, Nat Rev Gastro &
Hepatol
2019
Key molecular factors
1) Metabolic processes
2) Oxidative stress
3) Inflammatory processes
4) Activation of HSC, autophagy, cell death
Slide12Molecular pathogenesis
Singal
A, Am J
Gastroenterol
2014
Role of PNPLA3
Mann J, Nat Rev Gastro &
Hepatol
2017;
Sookolian
et al., Hepatology, 2011;
Rotman
et al., Hepatology, 2010
Prevalence of PNPLA3 SNP*
General population NAFLD NASH NASH-HCC
20-30% 30-50% 50% 60%
NASH-HCC
Meta-
analysis
: 2,937
patients
PNPLA3:
associated
with
risk
of HCC in NASH/ alcohol cirrosis: HR 1.67 (95% CI 1.27-2.21)
* MOA PNPLA3:
enzyme metabolites liver
tryglicerides
.
PNPLA3- SNP variant rs738409:
accumulation of lipid droplets
in the
hepatocytes
due to lack of ubiquitylation and of proteasomal degradation.
Slide13Targets and therapies
Targets for therapies and ongoing clinical trials for NASH
Targets for molecular therapies
Ongoing phase III trials
Friedman SL, Nature Medicine 2018
Management
recommendations
:
Control
Metabolic
Sd
Phase
III
improvement
of fibrosis/NASH- positive:
Pioglitazone
,
Obeticholic
acid
(FXR
agonist
),
Phase
II
ongoing
:
Cenicriviroc
(CCR2/5
inh
),
elafibranor
(PARP
inh
)
Slide14Molecular characterization of NASH-HCC
Epidemiology Molecular pathogenesis: from NAFLD to HCC
3. Molecular characterization of NASH-HCC a) Molecular subclasses and pathways
b) Are there unique drivers? c) Specific genotoxicity or cancer field effect?
Slide15Molecular events -
hepatocarcinogenesis
Llovet,
J. M. et al, Nat. Rev. Dis. Primers
2016
Slide16Signaling
pathways (mut
):Telomerase
maintenance: 60%Cell cycle
gene: 49%Wnt-B-
Catenin: 54%Epigenetic modifier: 32%Akt/mTOR: 51%MAPK: 43%
Signaling pathways
(other):
NOTCH: 30%TGF-Beta: 17%
MET: 50%IGF
Signaling : 15% (IGF2
epi-driver)
Schulze K, Nat Genetics 2015
Villanueva, Gastrotenterology 2012;
Coulouarn
et al,
Hepatology
2008
Molecular targets
for
HCC
Signaling pathways: molecular targets for new therapies.
Slide17Molecular classification of HCC
Llovet JM et al,
Nat
Rev
Clin Oncol 2018
Slide18NASH-HCC patients
Tumors
(n=53)
Expression
array
Signaling-Pathways in NASH-HCC tumors
Summary:
50% of NASH-HCC belong to the
proliferative
subclass whereas 50% belong to the
non-proliferative
subclass
Molecular classes are similar than in Hepatitis –HCC, but increase of S1-TGFB
Torrecilla S et al, ILCA-Abstract #9
Slide19Molecular characterization of NASH-HCC
Epidemiology Molecular pathogenesis: from NAFLD to HCC
3. Molecular characterization of NASH-HCC
a) Molecular subclasses and pathways b) Are there unique drivers?
c) Specific genotoxicity or cancer field effect?
Slide20Landscape of mutations in HCC
Vogelstein et al, Science 2013
35-40
Schulze K et al, Nat Genetics 2015
Genome
sequencing
in HCC (n=250)
Undruggable
mutations
Slide21Lanscape
of mutations and actionable drivers in HCC
Meta-analysis of 928 cases: 25% potential actionable targets!
Slide22Driver mutated genes in NASH-HCC
(n=50)
4
driver genes were altered in
≥10%
of NASH-HCC cases
ACVR2A was mutated in 10% of NASH-HCC
Median number of 3 mutated driver genes per sample (ranging from 0-10)
Landscape of mutations in NASH-HCC
Torrecilla S et al, ILCA-Abstract #9
Slide23Landscape of mutations in HCC
Torrecilla S et al, ILCA-Abstract #9
Slide24Molecular characterization of NASH-HCC
Epidemiology Molecular pathogenesis: from NAFLD to HCC
3. Molecular characterization of NASH-HCC
a) Molecular subclasses and pathways b) Are there unique drivers?
c) Specific genotoxicity or cancer field effect?
Slide25Mutational signatures in HCC
Dhanasekaran
R et al, Gastroenterology 2019
Slide26Mutational signatures
Prevalence of mutational signatures in NASH-HCC
Torrecilla S et al, ILCA-Abstract #9
Slide27Mutational signatures
Signature 3- significantly enriched in NASH-HCC
Torrecilla S et al, ILCA-Abstract #9
* In-house cohort and Public Dataset (ICGC)
Slide28Mutational signatures
Signature 3- associated with alterations in DNA repair
Ma J, et al. Nat Communications 2018
Slide29p<0.01
Gene
signature-poor
prognosis: # 186 genes
Gene Set Enrichment : 1. Inflammation 2. NF-KB signaling 3. interferon-related immune response 4. Oxidative stress and 5. Proliferative signals
(IL6, EGF)Training set (n=82)
Hoshida
et al, NEJM 2008
Cancer field effect
Cancer field in HCC - predicts
survival after resection
Slide30Cancer field effect
Moeini
A et al , Gastroenterology 2019 (in press)
Immune mediated- cancer field predicts
1st HCC occurrence
Immune-mediated
cancer
field
-
poor
prognosis: # 172 genes
Slide31Cancer field effect
Immune mediated- cancer field NASH vs NASH-HCC
Torrecilla S et al, ILCA-Abstract #9
Slide32Cancer field effect
Immune mediated- cancer field in NASH vs HBV/HCV
Torrecilla S et al, ILCA-Abstract #9
* In-house cohorts
Slide33Conclusions
The
global epidemic of obesity
is associated with an increase in the incidence of NASH-HCC
Molecular traits of NASH-HCC
, as opposed to hepatitis-related HCC, have been seldomly reported NASH tumors –compared to non-NASH HCC tumors- present:Similar molecular classes
Distinct mutational profile
a) Higher prevalence of
ACVR2A mutations (10% vs 2%)
b) Lower of TP53
mutations (18% vs 32%)
c) Three driver genes exclusively mutated in NASH-HCC (AMER1
,
E2F3
,
MOB3B
)
d) Higher frequency of
Mutational Signature 3
as their main genotoxic-related signature
Distinct cancer field effect traits : enrichment of
Immunossuppressed
Cancer-Field
More studies are needed to confirm these results & decipher the unique traits involved in the development of NASH-HCC