Adeno-Associated Virus 2-Mediated Hepatocellular Carcinoma is Very Rare in Korean Patients

Park, Kyoung-Jin; Lee, Jongan; Park, June Hee; Joh, Jae‐Won; Kwon, Choon Hyuck David; Kim, Jong Won

doi:10.3343/alm.2016.36.5.469

Cited by 14 publications

(15 citation statements)

References 13 publications

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“…AAV oncogenic integrations were identified in our cohort of European patients with HCC. They were also observed in the ICGC-Japan cohort in 3 HCC cases out of 268 HCC (1.1%),45 in 4 out of 334 HCC (1.2%) of the TCGA cohort34 and in 2 out of 289 HCC (0.7%) from Korea 56. Interestingly, the most frequent AAV integrated oncogenes are similar to HBV, that are, CCNA2 , CCNE1, TERT and KMT2B .…”

Section: Discussionmentioning

confidence: 69%

Adeno-associated virus in the liver: natural history and consequences in tumour development

Bella

Imbeaud

Péneau

et al. 2019

Gut

102

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ObjectiveAdeno-associated virus (AAV) is a defective mono-stranded DNA virus, endemic in human population (35%–80%). Recurrent clonal AAV2 insertions are associated with the pathogenesis of rare human hepatocellular carcinoma (HCC) developed on normal liver. This study aimed to characterise the natural history of AAV infection in the liver and its consequence in tumour development.DesignViral DNA was quantified in tumour and non-tumour liver tissues of 1461 patients. Presence of episomal form and viral mRNA expression were analysed using a DNAse/TaqMan-based assay and quantitative RT-PCR. In silico analyses using viral capture data explored viral variants and new clonal insertions.ResultsAAV DNA was detected in 21% of the patients, including 8% of the tumour tissues, equally distributed in two major viral subtypes: one similar to AAV2, the other hybrid between AAV2 and AAV13 sequences. Episomal viral forms were found in 4% of the non-tumour tissues, frequently associated with viral RNA expression and human herpesvirus type 6, the candidate natural AAV helper virus. In 30 HCC, clonal AAV insertions were recurrently identified in CCNA2, CCNE1, TERT, TNFSF10, KMT2B and GLI1/INHBE. AAV insertion triggered oncogenic overexpression through multiple mechanisms that differ according to the localisation of the integration site.ConclusionWe provided an integrated analysis of the wild-type AAV infection in the liver with the identification of viral genotypes, molecular forms, helper virus relationship and viral integrations. Clonal AAV insertions were positive selected during HCC development on non-cirrhotic liver challenging the notion of AAV as a non-pathogenic virus.

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Section: Discussionmentioning

confidence: 69%

Adeno-associated virus in the liver: natural history and consequences in tumour development

Bella

Imbeaud

Péneau

et al. 2019

Gut

102

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“…18,19 Three groups reported integration of the AAV2 genome in HCC. 7,20,21 Integrations of the AAV2 genome were detected 5.7% of French HCC cases. 20 It was reported that AAV2-positive tumors tended to occur in non-cirrhotic liver without known risk factors, suggesting that AAV2 genome integration might play an oncogenic role in some of the cases currently classified as risk-free.…”

Section: Structural Rearran Gements An D Virus Integration In H Ccmentioning

confidence: 99%

“…It was reported that AAV2‐positive tumors tended to occur in non‐cirrhotic liver without known risk factors, suggesting that AAV2 genome integration might play an oncogenic role in some of the cases currently classified as risk‐free. Integration of AAV2 was reported to be rarer (~1%) in Japanese (3/300) and Korean (2/289) cohorts …”

Section: Structural Rearrangements and Virus Integration In Hccmentioning

confidence: 99%

Molecular genomic landscapes of hepatobiliary cancer

Shibata

Arai²,

Totoki³

2018

Cancer Science

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Hepatocellular carcinoma (HCC) and biliary tract cancer are more frequent in East Asia including Japan than in Europe or North America. A compilation of 1340 multi‐ethnic HCC genomes, the largest cohort ever reported, identified a comprehensive landscape of HCC driver genes, comprised of three core drivers (TP53,TERT, and WNT signaling) and combinations of infrequent alterations in various cancer pathways. In contrast, five core driver genes (TP53,ARID1A,KRAS,SMAD4, and BAP1) with characteristic molecular alterations including fusion transcripts involving fibroblast growth factor receptor 2 and the protein kinase A pathway, and IDH1/2 mutation constituted the biliary tract cancer genomes. Consistent with their heterogeneous epidemiological backgrounds, mutational signatures and combinations of non‐core driver genes within these cancer genomes were found to be complex. Integrative analyses of multi‐omics data identified molecular classifications of these tumors that are associated with clinical outcome and enrichments of potential therapeutic targets, including immune checkpoint molecules. Translating comprehensive molecular‐genomic analysis together with further basic research and international collaborations are highly anticipated for developing precise and better treatments, diagnosis, and prevention of these tumor types.

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“…Despite some recent controversy regarding its role in cancer (Nault et al, 2015; Park et al, 2016; Srivastava and Carter, 2017), AAV is generally considered to be a nonpathogenic virus. As of April 2017, AAV has been used in 183 clinical trials (Edelstein, 2017) with no reported cancers.…”

Section: Introductionmentioning

confidence: 99%

A directed evolution approach to select for novel Adeno-associated virus capsids on an HIV-1 producer T cell line

Wooley

Sharma

Weinstein

et al. 2017

Journal of Virological Methods

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A directed evolution approach was used to select for Adeno-associated virus (AAV) capsids that would exhibit more tropism toward an HIV-1 producer T cell line with the long-term goal of developing improved gene transfer vectors. A library of AAV variants was used to infect H9 T cells previously infected or uninfected by HIV-1 followed by AAV amplification with wild-type adenovirus. Six rounds of biological selection were performed, including negative selection and diversification after round three. The H9 T cells were successfully infected with all three wild-type viruses (AAV, adenovirus, and HIV-1). Four AAV cap mutants best representing the small number of variants emerging after six rounds of selection were chosen for further study. These mutant capsids were used to package an AAV vector and subsequently used to infect H9 cells that were previously infected or uninfected by HIV-1. A quantitative polymerase chain reaction assay was performed to measure cell-associated AAV genomes. Two of the four cap mutants showed a significant increase in the amount of cell-associated genomes as compared to wild-type AAV2. This study shows that directed evolution can be performed successfully to select for mutants with improved tropism for a T cell line in the presence of HIV-1.

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Adeno-Associated Virus 2-Mediated Hepatocellular Carcinoma is Very Rare in Korean Patients

Cited by 14 publications

References 13 publications

Adeno-associated virus in the liver: natural history and consequences in tumour development

Adeno-associated virus in the liver: natural history and consequences in tumour development

Molecular genomic landscapes of hepatobiliary cancer

A directed evolution approach to select for novel Adeno-associated virus capsids on an HIV-1 producer T cell line

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