Unique Genomic Profile of Fibrolamellar Hepatocellular Carcinoma

Abstract

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 only be treated with surgery. We performed an integrative genomic analysis of a large series of patients with FLC to identify associated genetic factors. Methods 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 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 revealed 3 robust molecular classes of tumors: the proliferation class (51% of samples) had altered expression of genes that regulate proliferation and mTOR signaling activation; the inflammation class (26% of samples) had altered expression of genes that regulate inflammation and cytokine production; and the unannotated class (23% of samples) had a gene expression signature not previously associated with liver tumors. Expression of genes that regulate neuroendocrine function, as well has 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. Using this information, we identified a gene signature that is associated with patient survival time.

Genetic basis of hepatitis virus-associated hepatocellular carcinoma: linkage between infection, inflammation, and tumorigenesis

“…The recent development of the next-generation sequencing technologies provides novel strategies for analyzing the human genome and epigenome. Use of these new technologies has gradually begun to unveil the landscape of genetic and epigenetic aberrations of a variety of human tumors, including HCC [19][20][21][22][23][24][25][26][27][28][29][30]. In this article, we review the recent findings concerning genetic and epigenetic aberrations that accumulate during the development of hepatitis virus-associated HCC.…”

Methylome sequencing for fibrolamellar hepatocellular carcinoma depicts distinctive features

“…Indeed, in the Cornella et al study, which reported on 77 FLC, the presence of fusion transcript was found in 79% of cases. 5 Conversely, in the Graham et al study, rearrangements of the PRKACA locus were seen in all 19 FLC cases (100%). 9 Beside the specificity of DNAJB1-PRKACA transcript in support of diagnosis of FLC, the role of epigenetics alterations in shaping FLC identity and distinguishing p-FLC from other HCC subtypes remains limited.…”

“…4 Using transcriptomic profiling of a large set of p-FLC, m-FLC and HCC arising in non-cirrhotic liver, we and others recently showed that p-FLC harbor a unique signature characterized by the strong expression of specific neuroendocrine genes (i.e., PCSK1, DNER, CALCA and NTS). [5][6][7] Meanwhile, a recurrent DNAJB1-PRKACA chimeric transcript has been identified in a data set of 15 FLC cases (100%) suggesting that this genetic alteration contributes to tumor pathogenesis. 8 However, whether this translocation is pathognomonic for the diagnosis remains unclear.…”

A Gene Expression Signature Associated with Overall Survival in Patients with Hepatocellular Carcinoma Suggests a New Treatment Strategy

“…Hepatocellular carcinoma (HCC) is by far the most prevalent type, accounting for approximately 80%-85% of primary liver cancer cases (Singal and El-Serag, 2015), whereas cholangiocarcinoma (Ghouri et al, 2015) and fibrolamellar carcinoma (Lim et al, 2014;Cornella et al, 2015) occur at a frequency of only ∼14% and ∼1%, respectively. The epidemiology of HCC is well known, and in the vast majority of cases, it arises as a consequence of underlying liver disease, usually a viral hepatitis (Singal and El-Serag, 2015).…”