Unique genomic profile of fibrolamellar hepatocellular carcinoma

BACKGROUND & AIMS: Fibrolamellar hepatocellular carcinoma (FLC) is a rare primary hepatic cancer that develops in children and young adults without cirrhosis. Little is known about its pathogenesis, and it can be treated only with surgery. We performed an integrative genomic analysis of a large series of patients with FLC to identify associated genetic factors. METHODS: By using 78 clinically annotated FLC samples, we performed whole-transcriptome (n = 58), single-nucleotide polymorphism array (n = 41), and next-generation sequencing (n = 48) analyses; we also assessed the prevalence of the DNAJB1-PRKACA fusion transcript associated with this cancer (n = 73). We performed class discovery using non-negative matrix factorization, and functional annotation using gene-set enrichment analyses, nearest template prediction, ingenuity pathway analyses, and immunohistochemistry. The genomic identification of significant targets in a cancer algorithm was used to identify chromosomal aberrations, MuTect and VarScan2 were used to identify somatic mutations, and the random survival forest was used to determine patient prognoses. Findings were validated in an independent cohort. RESULTS: Unsupervised gene expression clustering showed 3 robust molecular classes of tumors: the proliferation class (51% of samples) had altered expression of genes that regulate proliferation and mammalian target of rapamycin signaling activation; the inflammation class (26% of samples) had altered expression of genes that regulate inflammation and cytokine enriched production; and the unannotated class (23% of samples) had a gene expression signature that was not associated previously with liver tumors. Expression of genes that regulate neuroendocrine function, as well as histologic markers of cholangiocytes and hepatocytes, were detected in all 3 classes. FLCs had few copy number variations; the most frequent were focal amplification at 8q24.3 (in 12.5% of samples), and deletions at 19p13 (in 28% of samples) and 22q13.32 (in 25% of samples). The DNAJB1-PRKACA fusion transcript was detected in 79% of samples. FLC samples also contained mutations in cancer-related genes such as BRCA2 (in 4.2% of samples), which are uncommon in liver neoplasms. However, FLCs did not contain mutations most commonly detected in liver cancers. We identified an 8-gene signature that predicted survival of patients with FLC. CONCLUSIONS: In a genomic analysis of 78 FLC samples, we identified 3 classes based on gene expression profiles. FLCs contain mutations and chromosomal aberrations not previously associated with liver cancer, and almost 80% contain the DNAJB1-PRKACA fusion transcript. By using this information, we identified a gene signature that is associated with patient survival time

MicroRNA-Based Classification of Hepatocellular Carcinoma and Oncogenic Role of miR-517a

Hepatocellular carcinoma (HCC) is a heterogeneous tumor that develops via activation of multiple pathways and molecular alterations. It has been a challenge to identify molecular classes of HCC and design treatment strategies for each specific subtype. MicroRNAs (miRNAs) are involved in HCC pathogenesis and their expression profiles have been used to classify cancers. We analyzed miRNA expression in human HCC samples to identify molecular subclasses and oncogenic miRNAs

Formalizing Argumentative Reasoning in a Possibilistic Logic Programming Setting with Fuzzy Unification ⋆

Possibilistic Defeasible Logic Programming (P-DeLP) is a logic programming language which combines features from argumentation theory and logic programming, incorporating the treatment of possibilistic uncertainty at the object-language level. In spite of its expressive power, an important limitation in P-DeLP is that imprecise, fuzzy information cannot be expressed in the object language. One interesting alternative for solving this limitation is the use of PGL +, a possibilistic logic over Gödel logic extended with fuzzy constants. Fuzzy constants in PGL + allow expressing disjunctive information about the unknown value of a variable, in the sense of a magnitude, modeled as a (unary) predicate. The aim of this article is twofold: firstly, we formalize DePGL +, a possibilistic defeasible logic programming language that extends P-DeLP through the use of PGL + in order to incorporate fuzzy constants and a fuzzy unification mechanism for them. Secondly, we propose a way to handle conflicting arguments in the context of the extended framework. Key words: Possibilistic logic, fuzzy constants, fuzzy unification, defeasible argumentation, warrant computatio

Fuzzy Argumentation System for Decision Support

International audienceWe introduce in this paper a quantitative preference based argumentation system relying on ASPIC argumentation framework and fuzzy set theory. The knowledge base is fuzzified to allow the experts to express their expertise (premises and rules) attached with grades of importance in the unit interval. Arguments are attached with a score aggregating the importance expressed on their premises and rules. Extensions are then computed and the strength of each of which can also be obtained based on its strong arguments. The strengths are used to rank fuzzy extensions from the strongest to the weakest one, upon which decisions can be made. The approach is finally used for decision making in a real world application within the EcoBioCap project

Argument-based Expansion Operators in Possibilistic Defeasible Logic Programming: Characterization and Logical Properties

Possibilistic Defeasible Logic Programming (P-DeLP) is a logic programming language which combines features from argumentation theory and logic programming, incorporating as well the treatment of possibilistic uncertainty and fuzzy knowledge at object-language level