studies

342A AASLD ABSTRACTS HEPATOLOGY, October, 2015
or de novo cancers (synchronic tumors) has direct implications
in treatment decision-making. We aimed to assess the genomic
heterogeneity of multifocal HCC using single-nucleotide polymorphism
(SNP), gene expression and mutations analyses.
Methods: Among 544 HCCs consecutively transplanted at
Mount Sinai Hospital, 18 patients with 2-3 non-satellite nodules/patient
were selected for this study. Formalin-fixed tissue
blocks and clinico-pathological parameters were collected for
each tumor. SNP array and gene expression profiling was generated.
Clonality was defined by measuring SNP profiles similarity
between two nodules. Prediction of previously published
signatures was performed using Nearest Template Prediction.
Mutational status of TERT promoter, ARID1A, CTNNB1, TP53,
AXIN1-2 genes was checked using TruSeqAmplicon. Results:
A total of 42 tumors have been analyzed. Most patients were
male (17/18, 95%) with HCV (10/18, 56%) or HBV infection
(6/18, 33%). Median tumor size was 3 cm (range 1.5-
6.5), satellites and vascular invasion were present in 3 (17%)
and 11 patients (61%), respectively. CNV profiles predicted
clonal tumors in 38% (6/16) and non-clonality in 63% of cases
(10/16), while the remaining 2 cases were not informative.
Clonal tumors were significantly associated with HCV infection
(5/6 vs 3/10, p=0.01), whereas all HBV-induced HCC were
synchronic tumors (0/6 vs 6/10, p=0.03). Clonal tumors were
significantly associated with presence of satellites and early
recurrence. Gene expression-based unsupervised clustering
revealed that each clonal tumor showed genetic proximity to its
paired tumor and clustered around the same node (6/6,100%)
as opposed to non-clonal (2/9, 22%). When exploring molecular
subclasses, while half of clonal tumors retained the molecular
fingerprint, the other half switched to more aggressive
subclasses. Conversely, all non-clonal tumors belonged to distinct
molecular subclasses. In order to explore if clonal tumors
retain the same driver trunk mutations, we tested five common
driver mutations in all HCC nodules. Identical trunk mutations
were identified only in clonal tumors. Conclusions: Among
multinodular HCC tumors, 40% of cases were classified as
clonal tumors (true IM) and the remaining 60% as non-clonal
synchronic tumors. Clonal tumors were significantly associated
with HCV infection, satellites and recurrence. Despite molecular
subclasses prediction revealed heterogeneous profile in
both clonal and non-clonal tumors, genetic proximity and trunk
driver mutations were similar in clonal tumors.
Disclosures:
Josep M. Llovet - Consulting: Bayer Pharmaceuticals, Bristol Myer Squibb, Boehringer-Ingelheim,
Eli Lilly Pharmaceuticals, Celsion, Biocompatibles, Novartis,
GlaxoSmithKline, Blueprint Medicines; Grant/Research Support: Bayer Pharmaceuticals,
Bristol Myers Squibb, Boehringer-Ingelheim
The following authors have nothing to disclose: Daniela Sia, Andrew Harrington,
Zhongyang Zhang, Genis Camprecios, Sara Toffanin, Agrin Moeini, M. Isabel
Fiel, Ke Hao, Monica Higuera, Oriana Miltiadous, Laia Cabellos, Helena Cornella,
Yujin Hoshida, Sander S. Florman, Myron E. Schwartz
254
Mixed hepatocellular-cholangiocarcinoma tumors:
stem-cell subtype and cholangiolocellular carcinoma are
unique molecular entities
Agrin Moeini 1,2 , Daniela Sia 2,1 , Zhongyang Zhang 3 , Genis
Camprecios 2 , M. Isabel Fiel 2 , Oriana Miltiadous 2 , Xiaochen
Sun 2 , Ke Hao 3 , Yujin Hoshida 2 , Swan N. Thung 2 , Augusto Villanueva
2 , Myron E. Schwartz 2 , Josep M. Llovet 2,1 ; 1 Liver Cancer
Translational Research Laboratory, Liver Unit, Institut d’Investigacions
Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic,
CIBERehd, Universitat de Barcelona, Barcelona, Spain; 2 Mount
Sinai Liver Cancer Program, (Divisions of Liver Diseases, Department
of Medicine, Department of Pathology, Recanati Miller
Transplantation Institute), Tisch Cancer Institute, Icahn School
of Medicine at Mount Sinai, New York, NY; 3 Icahn Institute for
Genomics and Multiscale Biology, Icahn School of Medicine at
Mount Sinai, New York, NY
Purpose: Provide a comprehensive analysis of the molecular
alterations of mixed hepatocellular-cholangiocarcinoma (HCCiCCA)
tumors, a rare type of primary liver cancer, by integrating
histological and genomic data. Methods: 19 patients
with mixed HCC-iCCA were classified based on histological
features and immunohistochemistry for specific hepatocyte
(HEP1, GPC3), biliary (CK7, CK19) and stem-cell markers
(EpCAM, NCAM, SALL4). Whole-genome gene-expression
and DNA copy number alterations (CNA) analysis were performed
(Illumina). Prevalent oncogenic mutations in HCC (TERT
promoter, TP53, CTNNB1) or iCCA (FGFR2-fusions, IDH1/2,
KRAS, BRAF) were screened. Results: Following WHO criteria,
HCC-iCCA samples were classified as classical (n=4), stem-cell
feature (n=9) and cholangiolocellular carcinoma (CLC) (n=6).
From the pathological standpoint, classical HCC-iCCA were
mainly EpCAM positive (3/4, 75%) with expression of hepatocyte
and biliary markers in the HCC-like and iCCA-like components,
respectively. Stem-cell subtypes were characterized
by SALL4 positive staining (7/9 vs 0/10 others, p