GUT:HBV integration promotes changes in local and long-range carcinogenic drivers of hepatocellular carcinoma

The study highlights that hepatitis B virus (HBC)-related hepatocellular carcinoma (HCC) can be promoted by different mechanisms.
of HBV integration in liver tissue revealed new HBV-related driver mechanisms associated with liver cancer.
HBV integration has a variety of direct carcinogenic effects, which is still an important challenge for follow-up in patients with HBV infection.
February 9, GUT reported on the results of HBC integration that promotes changes in local and long-range carcinogenic drivers of HCC.
this study provided a comprehensive analysis of the HBV genome in non-tumor and tumor liver tissue in a large number of patients, mainly from Europe and Africa, with the aim of accurately describing the relationship between HBV integration and viral and host genomics and clinical characteristics.
team created a new path to sequence hepatitis virus capture and sequencing in 177 HCC and 170 non-tumor liver tissue samples taken from 177 French HBV-positive patients.
in three selected tumor samples, complex integration was reconstructed using long-read sequencing or bio-nano-genome-wide mapping.
results show that HBV integration occurs in open chromosome regions and is associated with viral replication in the liver.
in 170 non-tumor liver tissues, high HBV copy numbers were associated with positive HBV DNA in women, young people, African or Asian regions, Serotype B surface antigens (HBsAg), hepatitis B e antigens (HBeAg) and HBV DNA.
, HBV copy numbers and HBV integration were less associated with supporting factors for chronic liver disease, such as active HCV or HDV infection, alcohol consumption, or metabolic syndrome.
18 percent of the samples contained replica HBV, which is rich in type A and showed more integration, suggesting that HBV replication and integration are interrelated processes.
addition, samples with a high number of HBV copies show frequent mutations in the substrate core promoter (BCP; A1762T/G1764A) or RT regions that facilitate virus replication.
, tumor and non-tumor tissues have different HBV integration spectral and HBV sequence structures.
the number of HBV integrations is highly related to the number of HBV copies per cell.
, however, although the number of copies of HBV per cell of the tumor was higher, the number of HBV break points per sample was lower than that of its corresponding non-tumor tissue (averages were 12 vs 39, p .lt;001).
this may reflect the high diversity of unique HBV integration in a large number of liver cells during infection, as well as the reduced diversity caused by the cloning amplification of transformed cells.
in both types of tissues, the most common HBV integration hotspots occur in the C-side region of the HBx gene around the DR1 sequence (1817-1836), corresponding to the end of the double-stranded linear DNA form of HBV.
in tumors, only a portion of the HBV genome corresponding to the integrated HBV DNA was detected and the HBx gene was often truncated.
In addition, the HBV genome in the tumor contained a greater number of structural variations (missing, repeating, inverted) in the viral sequence, and only 3% (17/514) of structural variation was observed in the adjacent liver tissue of the tumor.
, the positioning and orientation of HBV/human junctions in the human genome indicate frequent redoing of chromosomes in tumors, suggesting that the integration process or post-integration structural modification is more complex than non-tumor liver tissue.
integration of HBV in non-tumor tissues is associated with viral replication and is more common in large high expression genes.
detection rate of HBV replication in non-tumor tissues (7%:18%, p .lt;0.001).
results suggest that HBV integration in non-tumor and tumor liver tissue may reflect different viral dynamics and selection processes that are not directly related.
HBV integration often limits human dyed weight row, and its integrated cloning options are associated with two different carcinogenic mechanisms.
HBV genome can be integrated into cancer-driven genes and has a smooth activation effect.
, HBV insertion mutations develop into HCC, the integration of viral enhancers near cancer-causing genes can lead to strong overexposing of cancer genes.
, the researchers found that frequent dyed weight rows at HBV integration points led to changes in distant cancer-driven genes (TERT, TP53, MYC).
HBV-induced cancer may also be driven by changes in the number of frequent copies of cancer-driven genes associated with distant virus integration.
confirmed that TERT initiaters are the main HBV integration hotspots in HCC.
interestingly, CCN-HCC showed changes in TRT initiaters, while KMT2B-integrated HCC did not show changes in TRT initiaters or any other drive genes, suggesting different carcinogenic processes.
addition, HBV integration is an independent prognossis factor for HBV-related liver cancer.
tumors with high number of HBV integrations had poor prognosms.
not related to other characteristics such as tumor size, microvascular immersion, differentiation and transcription group.
interestingly, these patients are significantly younger and carry a high proportion of HBV integration in the tumor, which affects cancer-driven genes such as TRT (p s 0.02) by inserting a promoter, TP53 (p -lt;0.001) or MYC (p s 0.03).
HBV-related CNA.
HBV integration has direct clinical significance because of the large number of HCC gene insertions in most young patients and the poor prognostics.
, HBV integration in non-tumor tissues reflects active replication of the virus and the expansion of liver cells in liver tissue, while the expression of inflammatory-related genes is low.
, on the other hand, the HBV integration sequence in the tumor highlights cells with functional selection that have HBV-related structural rearms or insert mutages as driver changes.
Because cloned, integrated non-tumor tissue shows a reduction in genes associated with inflammatory response, this suggests that some liver cells that have a selective advantage in avoiding the immune antiviral response may experience active proliferation and gain protective characteristics for malignant transformation.
, the study highlighted the complexity of the interaction between HBV integration, HBV replication, and chromosomal instability during liver cancer, among other supporting factors.
, aflatoxin B1 exposure, which is mainly present in Africa, can directly trigger the development of HBV-related HCC through the TP53 R249S mutation.
on the other hand, HDV infection limits HBV replication and virus integration, but accelerates chronic inflammation and fibrosis in young patients.
important, a series of studies by the team have shown that the number of HBV integrations in tumors is the only marker of viral characteristics associated with poor prognosmology.
large amount of HBV integration was associated with viral replication and poor prognosis of tumors in non-tumor liver tissue.
suggests that effective antiviral therapy is needed early in the course of the disease to limit the number of HBV integrations and to combat HCC development directly related to HBV.
, the heterogeneity of these tumors and molecular identification are important in identifying new specific treatment opportunities.
Reference：Péneau C, Imbeaud S, La Bella T, et al. Hepatitis B virus integrations promote local and distant oncogenic driver alterations in hepatocellular carcinoma. Gut Publiced Online First: 09 February 2021.doi: 10.1136/gutjnl-2020-323153MedSci Original Source: MedSci Original Copyright Statement: All on this website Text, images and audio-visual materials indicating "Source: Mets Medicine" or "Source: MedSci Original" are copyrighted by Mets Medicine and may not be reproduced by any media, website or individual without authorization, and shall be reproduced with the words "Source: Mets Medicine".
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