Transcriptomic characterization of fibrolamellar hepatocellular carcinoma

Abstract

Fibrolamellar hepatocellular carcinoma (FLHCC) tumors all carry a deletion of ∼400 kb in chromosome 19, resulting in a fusion of the genes for the heat shock protein, DNAJ (Hsp40) homolog, subfamily B, member 1, DNAJB1, and the catalytic subunit of protein kinase A, PRKACA. The resulting chimeric transcript produces a fusion protein that retains kinase activity. No other recurrent genomic alterations have been identified. Here we characterize the molecular pathogenesis of FLHCC with transcriptome sequencing (RNA sequencing). Differential expression (tumor vs. adjacent normal tissue) was detected for more than 3,500 genes (log2 fold change ≥1, false discovery rate ≤0.01), many of which were distinct from those found in hepatocellular carcinoma. Expression of several known oncogenes, such as ErbB2 and Aurora Kinase A, was increased in tumor samples. These and other dysregulated genes may serve as potential targets for therapeutic intervention.

RNAi High-Throughput Screening of Single- and Multi-Cell-Type Tumor Spheroids: A Comprehensive Analysis in Two and Three Dimensions

“…Most of these genes have been shown to be associated with increased differentiation, and in fact, FRK functions as an oncogene. 19 Knockdown of these genes is purported to be associated with reduced viability, and this is indeed what we see in our 3D models. Surprisingly, these were not associated with an SCTS effect.…”

Advancements in Next-Generation Sequencing

“…Sequencing of the cohort revealed that all of the tumors contained a novel gene fusion between DNAJB1 and PRKACA, producing a fusion protein that retains kinase activity. Elana was a coauthor on two publications describing this work (51,110). This example highlights not only how powerful the ubiquitous access to sequencing tools has become, but also how accepted they are becoming as a transformative tool in health care.…”

Fibrolamellar carcinoma as a distinct subtype of hepatocellular carcinoma: molecular genetics features, diagnostics and treatment prospects

“…Одно из первых исследований по анализу транскриптома ФлК подтвердило закономер ности, описанные ранее, -гиперактивацию сигнальных каскадов RAS, MAPK, PI3K, EGFR, mTOR [25].…”

“…Simon и соавторы [25] продемонстрировали значитель ное увеличение экспрессии генов, кодирующих коллагены различных типов, в том числе тех классов, которые ассо циированы с канцерогенезом. Кроме того, было выявлено повышение экспрессии генов, кодирующих белки, уча ствующие в межклеточных взаимодействиях: коннексины (GJC1 и GJA5), альфа субъединицы интегринов, компо ненты адгезионных контактов, например кадгерин 13, ги перэкспрессия которого была ранее описана при ГЦР.…”