studies

HEPATOLOGY, VOLUME 62, NUMBER 1 (SUPPL) AASLD ABSTRACTS 275A
Disclosures:
Andrew D. Cherniack - Grant/Research Support: Bayer AG
Lewis R. Roberts - Grant/Research Support: Bristol Myers Squibb, ARIAD Pharmaceuticals,
BTG, Wako Diagnostics, Inova Diagnostics, Gilead Sciences, Five
Prime Therapeutics
The following authors have nothing to disclose: Renumathy Dhanasekaran, Kyle
Covington, Jennifer Watt, Daniel R. O’Brien, Ju-Seog Lee, Chad Creighton,
Donna M. Munzy, David A. Wheeler
130
Targeting the TGF-β Pathway Increases Patient Survival
for Hepatocellular Cancer
Jian Chen 1 , Jiun-Sheng Chen 1 , Wilma Jogunoori 1 , Young Jin Gi 1 ,
Yun Seong Jeong 1 , Xiaoping Su 1 , Asif Rashid 1 , Bibhuti Mishra 2 ,
Jon White 2 , Milind Javle 1 , Marta L. Davila 1 , John R. Stroehlein 1 ,
Xuemei Wang 1 , Jeffrey S. Morris 1 , Rehan Akbani 1 , Lopa Mishra 1 ;
1 The University of Texas MD Anderson Cancer Center, Houston,
TX; 2 Institute of Clinical Research, Veterans Affairs Medical Center,
Washington DC, DC
Liver cancers that include hepatocellular cancer (HCC) and
intrahepatic cholangiocarcinoma are among the most challenging
and lethal malignancies with a degree of complexity seldom
seen in other cancers. Patients with HCC have a poor survival
of 9-11 months. However, key driver pathways and identifying
specific populations responsive to targeted therapeutics have
remained elusive. Recent clinical studies show that targeting
TGF-β in patients with high TGF-β level improves survival up
to 21 months. Therefore, we hypothesized that genomic, transcriptomic
profiles coupled with mouse mutants and functional
analyses may identify specific patients with HCC with a high
response rate to targeting TGF-β and present an attractive new
treatment strategy. Methods and Results: (1) We analyzed the
transcriptome of 488 hepatocellular cancers and screened for
mutations in the TGF-β pathway in 202 HCCs from The Cancer
Genome Atlas (TCGA). We found aberrant TGF-β superfamily
in 72% of HCC with mutations in 38%, the greatest number
being for the Smad adaptor β2SP (6%). (2) Increased levels of
TGF-β genes were designated as an “activated” signature that
is associated with hepatic fibrosis. Decreased levels of TGF-β
genes were defined as an “inactivated” signature, which was
associated with the loss of TGF-β tumor suppressor function.
HCCs characterized by the “inactivated” TGF-β signature were
associated with a significantly poorer survival particularly in
early stage HCCs, compared to HCCs with the “activated”
TGF-β signature (p=0.0027). (3) The TGF-β pathway is statistically
significantly associated with DNA repair genes. (4)
We performed (80x) whole-genome sequence analysis of eight
additional HCCs to define the role of TGF-β in their development
and characterize a potential novel “driver mutations” in
HCV- and alcohol-associated HCC. (5) Further functional analyses
were performed in mouse mutants in the TGF-β pathway
that spontaneously develop HCC, patient derived xenografts,
and human cell lines. Increased levels of TGF-β associated-E3
ligases, including KEAP1, and PJA1 were found in 20% of
HCCs. Targeting these E3 ligases revealed a strong response
using patient derived xenografts. Conclusions: The molecular
signatures of the TGF-β pathway we characterize here appear
to have prognostic significance. The additional association
with the DNA repair pathway supports new approaches to
developing biomarkers. TGF-β and TGF-β-associated-E3 ligases
are activated in distinct groups of liver cancer patients. It may
be possible to identify subsets of patients, defined by the activation
or inactivation of TGF-β signaling, who may respond more
effectively to specific treatments.
Disclosures:
The following authors have nothing to disclose: Jian Chen, Jiun-Sheng Chen,
Wilma Jogunoori, Young Jin Gi, Yun Seong Jeong, Xiaoping Su, Asif Rashid,
Bibhuti Mishra, Jon White, Milind Javle, Marta L. Davila, John R. Stroehlein,
Xuemei Wang, Jeffrey S. Morris, Rehan Akbani, Lopa Mishra
131
A Study for the Risk Factors of Hepatocellular Carcinoma
in Cirrhotic Patients with Chronic Hepatitis B
Yuanqing Zhang 1 , Lijun Peng 1,2 , Yirong Cao 1 , Zhiping Zeng 1 ,
Yujing Wu 1 , Hong Shi 1 , Shiyao Chen 1 , Jiyao Wang 1 , Scott L.
Friedman 1,3 , John J. Sninsky 1,4 , Jinsheng Guo 1 ; 1 Division of Digestive
Diseases, Zhong Shan Hospital, Fu Dan University, Shanghai,
China; 2 Department of Gastroenterology, Linyi People’s Hospital,
Linyi, China; 3 Division of Liver Diseases,, Mount Sinai Hospital,
Icahn School of Medicine at Mount Sinai, New York, NY; 4 Celera/Quest
Diagnostics, Alameda, CA
Background and Aims: Chronic hepatitis B virus infection and
cirrhosis are important risk factors for hepatocellular carcinoma
(HCC), however the HCC risk can vary widely among individuals.
The aim of this study was to identify the clinical factors
and host genetic single nucleotide polymorphisms (SNPs) that
are associated with HCC risk in cirrhotic patients with CHB.
Methods: Data from 949 Chinese Han patients with chronic
HBV infection were analyzed by single and multivariate logistic
regression analysis in cirrhotic patients without (n = 281) and
with HCC (n = 434) to identify the clinical factors associated
with HCC risk. In a parallel study, DNA was extracted from
879 chronic HBV patients including non-cirrhotic HBV carriers
and CHB patients (n = 234), cirrhotic patients without (n =
257) and with HCC (n = 388) for genotyping of ten candidate
SNPs using polymerase chain reaction-ligase detection
reaction method. The correlations between the candidate SNPs
and HCC risk were analyzed by chi-square test followed by
logistic regression analysis. Results: 1. Ineffective antiviral treatment
(OR=5.2), fatty liver (OR=3.4), family history of HCC
(OR=2.3), drinking history (OR=2.2), and age≥50 (OR=1.8)
were independent risk factors for HCC in cirrhotic patients with
CHB. Longer HBV infection increased the HCC risk whereas
sustained virologic suppression significantly lowered HCC
risk compared to those without enough response or untreated
patients, especially in patients with decompensated cirrhosis.
Even after achieving viral suppression, 36.5% (62/170) of cirrhotic
patients with CHB still developed HCC. Fatty liver, family
history of HCC and HBV infection were significantly associated
with the HCC development in these patients. 2. After adjusted
for influencing factors, TLR4 rs11536889 was found to be a
protective factor (OR for CC vs. GG+GC or GG =0.4 and
0.6, respectively) whereas SPP1 rs2853744 (OR for TT vs. GG
and GT+TT vs. GG =1.9 and 3.1, respectively) and AP3S2
rs2290351 (OR for GA+AA or GA vs. GG =2.5 and 2.9,
respectively) were risk factors of HCC in cirrhotic patients with
CHB. In cirrhotic patients with CHB and drinking history, MLEC
rs7976497 (OR for TT vs. CC=2.8, CT+TT vs. CC=3.6) and
SOCS3 rs4969168 (OR for GG vs. AA=2.4) were found to be
risk factors of HCC. Conclusion: Ineffective antiviral treatment,
fatty liver, family history of HCC, drinking history and age≥50
are risk factors for HCC. Sustained suppression of HBV does
not remove the risk of HCC. Specific host genetic factors may
impact on HCC development in cirrhotic patients with CHB
including a protective SNP in TLR4, and risk SNPs in SPP1,
AP3S2, MLEC, and SOCS3.