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Mécanismes moléculaires et conséquences oncogéniques des intégrations du Virus de l’Hépatite B dans les tissus hépatiques

Abstract : Despite the existence of an effective vaccine and of treatments that suppress viral replication, Hepatitis B Virus (HBV) infection remains one of the most frequent chronic diseases. 39% of HBV-related deaths are associated with the development of hepatocellular carcinoma (HCC), the most common primary liver cancer and the third leading cause of cancer death worldwide. HBV is indeed the main risk factor of HCC development in patients who generally already have a liver cirrhosis induced by the infection. However, the fact that some HBV-related HCC occur without chronic inflammation underlines the direct oncogenic properties of this DNA virus, which can promote hepatocyte cell transformation through integration into the human genome. This project aimed to describe the HBV genomes in tumor and non-tumor liver tissues from 177 patients, mostly with African and European origin, using viral capture and next-generation sequencing techniques, and characterized viral integrations according to the genetic and clinical data of the patients. We showed that non-tumor tissues contain more frequently replicating HBV DNA and a higher number of insertions, mainly located in open chromatin regions but without direct functional consequences. In tumors, on the other hand, HBV integrations are often clonal and enriched in proximity of genes involved in hepatocarcinogenesis such as TERT (in one-third of HBV-related HCC), CCNE1, or KMT2B, and can directly lead to tumor development by activating these genes in cis. HBV integrations in CCNA2 or CCNE1, for example, generate replicative stress and a specific signature of structural rearrangements, thus promoting the development of aggressive HCC in the absence of cirrhosis. We also described a novel oncogenic mechanism associated with HBV integrations based on rearrangements of the human genome delimited by integrated viral sequences, which induce copy number alterations of distant "driver" genes such as TP53 or MYC. We have therefore further characterized the viral integrations of HBV in HCC, but also those of the adeno-associated virus (AAV) which can also integrate into human DNA and promote tumor development through insertional mutagenesis by altering the same genes as HBV (TERT, CCNA2, CCNE1, KMT2B).
Keywords : Cancer genomics
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https://theses.hal.science/tel-03768818
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Submitted on : Monday, September 5, 2022 - 1:02:13 AM
Last modification on : Tuesday, October 18, 2022 - 4:31:11 AM

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  • HAL Id : tel-03768818, version 1

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Camille Péneau. Mécanismes moléculaires et conséquences oncogéniques des intégrations du Virus de l’Hépatite B dans les tissus hépatiques. Cancer. Université Paris Cité, 2020. Français. ⟨NNT : 2020UNIP7101⟩. ⟨tel-03768818⟩

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