Comprehensive analysis of The Cancer Genome Atlas reveals a unique gene and non-coding RNA signature of fibrolamellar carcinoma

Dinh, Timothy A.; Vitucci, Eva C.M.; Wauthier, Eliane; Graham, Rondell P.; Pitman, Wendy A.; Oikawa, Tsunekazu; Chen, Mengjie; Silva, Grace O.; Greene, Kevin; Torbenson, Michael; Reíd, Lola M.; Sethupathy, Praveen

doi:10.1038/srep44653

Cited by 81 publications

(91 citation statements)

References 65 publications

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“…Interestingly, the fusion gene is the only known recurrent genomic aberration in FL-HCC, where it has been identified in 80-100% of patients in various studies. By contrast, this aberration has not been reported in any other cancer 7,9,10 . Mutations in other genes have been detected in FL-HCC tumors along with the DNAJB1–PRKACA alteration 8,11,12 .…”

Section: Introductioncontrasting

confidence: 56%

CRISPR/Cas9 Engineering of Adult Mouse Liver Demonstrates That the Dnajb1–Prkaca Gene Fusion Is Sufficient to Induce Tumors Resembling Fibrolamellar Hepatocellular Carcinoma

et al. 2017

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Background & Aims Fibrolamellar hepatocellular carcinoma (FL-HCC) is a primary liver cancer that predominantly affects young adults with no underlying liver disease. A somatic, 400 Kb deletion on chromosome 19 that fuses part of the DnaJ heat shock protein family (Hsp40) member B1 gene (DNAJB1) to the protein kinase cAMP-activated catalytic subunit alpha gene (PRKACA) has been repeatedly identified in patients with FL-HCC. However, the DNAJB1–PRKACA gene fusion has not been shown to induce liver tumorigenesis. We used the CRISPR/Cas9 technique to delete in mice the syntenic region on chromosome 8 to create a Dnajb1–Prkaca fusion and monitored the mice for liver tumor development. Methods We delivered CRISPR/Cas9 vectors designed to juxtapose exon 1 of Dnajb1 with exon 2 of Prkaca to create the Dnajb1–Prkaca gene fusion associated with FL-HCC, or control Cas9 vector, via hydrodynamic tail vein injection to livers of 8 week-old female FVB/N mice. These mice did not have any other engineered genetic alterations and were not exposed to liver toxins or carcinogens. Liver tissues were collected 14 months after delivery; genomic DNA was analyzed by PCR to detect the Dnajb1–Prkaca fusion, and tissues were characterized by histology, immunohistochemistry, RNA sequencing, and whole-exome sequencing. Results Livers from 12 of the 15 mice given the vectors to induce the Dnajb1–Prkaca gene fusion, but none of the 11 mice given the control vector, developed neoplasms. The tumors contained the Dnajb1–Prkaca gene fusion and had histologic and cytologic features of human FL-HCCs: large polygonal cells with granular, eosinophilic, and mitochondria-rich cytoplasm, prominent nucleoli, and markers of hepatocytes and cholangiocytes. In comparing expression levels of genes between the mouse tumor and non-tumor liver cells, we identified changes similar to those detected in human FL-HCC, which included genes that affect cell cycle and mitosis regulation. Genomic analysis of mouse neoplasms induced by the Dnajb1–Prkaca fusion revealed a lack of mutations in genes commonly associated with liver cancers, as observed in human FL-HCC. Conclusions Using CRISPR/Cas9 technology, we found generation of the Dnajb1–Prkaca fusion gene in wild-type mice to be sufficient to initiate formation of tumors that have many features of human FL-HCC. Strategies to block DNAJB1–PRKACA might be developed as therapeutics for this form of liver cancer.

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Section: Introductioncontrasting

confidence: 56%

CRISPR/Cas9 Engineering of Adult Mouse Liver Demonstrates That the Dnajb1–Prkaca Gene Fusion Is Sufficient to Induce Tumors Resembling Fibrolamellar Hepatocellular Carcinoma

et al. 2017

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“…Слитный транскрипт DNAJB1PRKАCA специфичен для ФлК и не выявляется в других типах опухолей печени или в стромальных клетках ФлК [27,35] Злокачественные опухоли www.malignanttumours.org…”

Section: хромосомная перестройка Dnajb1-prkаca -специфический маркер флкunclassified

“…При анализе данных полнотранскриптомного секвени рования из базы TCGA (The Cancer Genome Atlas) было про ведено сравнение около 9100 образцов опухолей 30 раз личных этиологий и также подтверждена специфичность химерного транскрипта DNAJB1PRKCA для ФлК [35].…”

Section: хромосомная перестройка Dnajb1-prkаca -специфический маркер флкunclassified

“…Являясь ключевым драйвером развития опухоли, химерный белок DNAJB1PRKCA может быть использован для дифференциальной диагностики ФлК, поскольку вы соко специфичен для конкретного типа опухолей и вы является методами, рутинно адаптируемыми для кли нической практики. Согласно данным опубликованных исследований [34,35] Abstract: Fibrolamellar carcinonoma (FLC) was described in 1956 as a separate subtype of hepatocellular carcinoma (HCC) that affects young adults without underling liver diseases. Morphologically FLC is characterized as HCC with large cells, gross nucleus and fibrous collagen bands organized into branched net.…”

Section: заключениеunclassified

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

Shavochkina¹,

Кустова²,

Лазаревич³

2017

Zlokač. opuholi

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“…To further explore the corresponding miRNAs and genes associated with PVT1, the GEO and TCGA databases were used to further investigate the differentially expressed miRNAs or genes [24][25][26]. The differentially expressed miRNAs in the GEO database were chosen using the described vote-counting strategy [27].…”

Section: Identification Of the Corresponding Mirnas Or Genes Associatmentioning

confidence: 99%

A Preliminary Investigation of PVT1 on the Effect and Mechanisms of Hepatocellular Carcinoma: Evidence from Clinical Data, a Meta-Analysis of 840 Cases, and In Vivo Validation

Wen

Zhang

Huang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Hepatocellular carcinoma (HCC) remains a difficult problem that significantly affects the survival of the afflicted patients. Accumulating evidence has demonstrated the functions of long non-coding RNA (lncRNA) in HCC. In the present study, we aimed to explore the potential roles of PVT1 in the tumorigenesis and progression of HCC. Methods: In this study, quantitative reverse transcription-polymerase chain reaction (RT-qPCR) was applied to detect the differences between PVT1 expression in HCC tissues and cell lines. Then, the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were searched to confirm the relationship between PVT1 expression and HCC. Moreover, a meta-analysis comprising TCGA, GEO, and RT-qPCR was applied to estimate the expression of PVT1 in HCC. Then, cell proliferation was evaluated in vitro. A chicken chorioallantoic membrane (CAM) model of HCC was constructed to measure the effect on tumorigenicity in vivo. To further explore the sponge microRNA (miRNA) of PVT1 in HCC, we used TCGA, GEO, a gene microarray, and target prediction algorithms. TCGA and GEO and the gene microarray were used to select the differentially expressed miRNAs, and the different target prediction algorithms were applied to predict the target miRNAs of PVT1. Results: We found that PVT1 was markedly overexpressed in HCC tissue than in normal liver tissues based on both RT-qPCR and data from TCGA, and the overexpression of PVT1 was closely related to the gender and race of the patient as well as to higher HCC tumor grades. Also, a meta-analysis of 840 cases from multiple sources (TCGA, GEO and the results of our in-house RT-qPCR) showed that PVT1 gained moderate value in discriminating HCC patients from normal controls, confirming the results of RT-qPCR. Additionally, the upregulation of PVT1 could promote HCC cell proliferation in vitro and vivo. Based on the competing endogenous RNA (ceRNA) theory, the PVT1/miR-424-5p/INCENP axis was finally selected for further research. The in silico prediction revealed that there were complementary sequences between PVT1 and miR-424-5p as well as between miR-424-5p and INCENP. Furthermore, a negative correlation trend was found between miR-424-5p and PVT1 based on RT-qPCR, whereas a positive correlation trend was found between PVT1 and INCENP based on data from TCGA. Also, INCENP small interfering RNA (siRNA) could significantly inhibit cell proliferation and viability. Conclusions: We hypothesized that PVT1 could affect the biological function of HCC cells via targeting miR-424-5p and regulating INCENP. Focusing on the new insight of the PVT1/miR-424-5p/INCENP axis, this study provides a novel perspective for HCC therapeutic strategies.

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Comprehensive analysis of The Cancer Genome Atlas reveals a unique gene and non-coding RNA signature of fibrolamellar carcinoma

Cited by 81 publications

References 65 publications

CRISPR/Cas9 Engineering of Adult Mouse Liver Demonstrates That the Dnajb1–Prkaca Gene Fusion Is Sufficient to Induce Tumors Resembling Fibrolamellar Hepatocellular Carcinoma

CRISPR/Cas9 Engineering of Adult Mouse Liver Demonstrates That the Dnajb1–Prkaca Gene Fusion Is Sufficient to Induce Tumors Resembling Fibrolamellar Hepatocellular Carcinoma

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

A Preliminary Investigation of PVT1 on the Effect and Mechanisms of Hepatocellular Carcinoma: Evidence from Clinical Data, a Meta-Analysis of 840 Cases, and In Vivo Validation

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