ObjectiveInfection by HBV is the main risk factor for hepatocellular carcinoma (HCC) worldwide. HBV directly drives carcinogenesis through integrations in the human genome. This study aimed to precisely characterise HBV integrations, in relation with viral and host genomics and clinical features.DesignA novel pipeline was set up to perform viral capture on tumours and non-tumour liver tissues from a French cohort of 177 patients mainly of European and African origins. Clonality of each integration event was determined with the localisation, orientation and content of the integrated sequence. In three selected tumours, complex integrations were reconstructed using long-read sequencing or Bionano whole genome mapping.ResultsReplicating HBV DNA was more frequently detected in non-tumour tissues and associated with a higher number of non-clonal integrations. In HCC, clonal selection of HBV integrations was related to two different mechanisms involved in carcinogenesis. First, integration of viral enhancer nearby a cancer-driver gene may lead to a strong overexpression of oncogenes. Second, we identified frequent chromosome rearrangements at HBV integration sites leading to cancer-driver genes (TERT, TP53, MYC) alterations at distance. Moreover, HBV integrations have direct clinical implications as HCC with a high number of insertions develop in young patients and have a poor prognosis.ConclusionDeep characterisation of HBV integrations in liver tissues highlights new HBV-associated driver mechanisms involved in hepatocarcinogenesis. HBV integrations have multiple direct oncogenic consequences that remain an important challenge for the follow-up of HBV-infected patients.
Cyclins A2 and E1 regulate the cell cycle by promoting S phase entry and progression. Here, we identify a hepatocellular carcinoma (HCC) subgroup exhibiting cyclin activation through various mechanisms including hepatitis B virus (HBV) and adeno-associated virus type 2 (AAV2) insertions, enhancer hijacking and recurrent CCNA2 fusions. Cyclin A2 or E1 alterations define a homogenous entity of aggressive HCC, mostly developed in non-cirrhotic patients, characterized by a transcriptional activation of E2F and ATR pathways and a high frequency of RB1 and PTEN inactivation. Cyclin-driven HCC display a unique signature of structural rearrangements with hundreds of tandem duplications and templated insertions frequently activating TERT promoter. These rearrangements, strongly enriched in early-replicated active chromatin regions, are consistent with a break-induced replication mechanism. Pan-cancer analysis reveals a similar signature in BRCA1-mutated breast and ovarian cancers. Together, this analysis reveals a new poor prognosis HCC entity and a rearrangement signature related to replication stress.
The aberrant expression of miR-221 is a hallmark of human cancers, including hepatocellular carcinoma (HCC), and its involvement in drug resistance, together with a proved efficacy of anti-miR-221 molecules, strengthen its role as an attractive target candidate in the oncologic field. The discovery of biomarkers predicting the response to treatments represents a clinical challenge in the personalized treatment era. This study aimed to investigate the possible role of miR-221 as a circulating biomarker in HCC patients undergoing sorafenib treatment as well as to evaluate its contribution to sorafenib resistance in advanced HCC. A chemically induced HCC rat model and a xenograft mouse model, together with HCC-derived cell lines were employed to analyze miR-221 modulation by Sorafenib treatment. Data from the functional analysis were validated in tissue samples from surgically resected HCCs. The variation of circulating miR-221 levels in relation to Sorafenib treatment were assayed in the animal models and in two independent cohorts of patients with advanced HCC. MiR-221 over-expression was associated with Sorafenib resistance in two HCC animal models and caspase-3 was identified as its target gene, driving miR-221 anti-apoptotic activity following Sorafenib administration. Lower pre-treatment miR-221 serum levels were found in patients subsequently experiencing response to Sorafenib and an increase of circulating miR-221 at the two months assessment was observed in responder patients. MiR-221 might represent a candidate biomarker of likelihood of response to Sorafenib in HCC patients to be tested in future studies. Caspase-3 modulation by miR-221 participates to Sorafenib resistance. .
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.
Tivantinib was initially reported as a selective MET inhibitor and is under phase III evaluation in "MET-high" hepatocellular carcinoma (HCC) patients. However, it has been also proposed as an antimitotic agent. We aimed to evaluate the antitumor effect of tivantinib in HCC cells by combining pharmacologic and molecular profiling. Sensitivity to tivantinib, JNJ-38877605, PHA-665752, vinblastine, and paclitaxel was tested in a panel of 35 liver cancer cell lines analyzed with exome sequencing, mRNA expression of 188 genes, and protein expression. Drug effect was investigated by Western blot analysis and mitotic index quantification. Expression of candidate biomarkers predicting drug response was analyzed in 310 HCCs. Tivantinib sensitivity profiles in the 35 cell lines were similar to those obtained with antimitotic drugs. It induced blockage of cell mitosis, and high cell proliferation was associated with sensitivity to tivantinib, vinblastine, and paclitaxel. In contrast, tivantinib did not suppress MET signaling, and selective MET inhibitors demonstrated an antiproliferative effect only in MHCC97H, the unique cell line displaying gene amplification. HCC tumors with high expression of cell proliferation genes defined a group of patients with poor survival. Interestingly, highly proliferative tumors also demonstrated high MET expression, likely explaining better therapeutic response of MET-high HCC patients to tivantinib. Tivantinib acts as an antimitotic compound, and cell proliferation markers are the best predictors of its antitumor efficacy in cell lines. Ki67 expression should be tested in clinical trials to predict tivantinib response. .
<p>Supplementary Table S1. Characteristics of surgical HCC patients analysed in this study. Supplementary Table S2. Patients assessed for circulating miR-221. Supplementary Table S3. Primer sequences and PCR conditions for the cloning experiment. Supplementary Table S4. Primer sequences and PCR conditions. Supplementary Table S5. Antibodies used in Western blot analysis.</p>
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