# Analysis of hepatitis B virus integration identifies KMT2B as a novel cancer‐related gene in pancreatic cancer

## TL;DR

This study finds that hepatitis B virus integration in pancreatic cancer cells affects the KMT2B gene, promoting cancer growth through the PI3K/Akt pathway.

## Contribution

KMT2B is identified as a novel cancer-related gene in pancreatic cancer due to HBV integration and its role in activating the PI3K/Akt pathway.

## Key findings

- HBV integration occurs in about one-third of HBV DNA-positive pancreatic cancer tissues.
- KMT2B is frequently targeted by HBV integration and is upregulated in pancreatic cancer.
- KMT2B promotes cancer progression by regulating FYN through histone H3K4 trimethylation and activating the PI3K/Akt pathway.

## Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with few well‐established risk factors. Emerging epidemiological evidence suggests a link between hepatitis B virus (HBV) infection and PDAC. However, the underlying mechanisms remain unclear.

High‐throughput sequencing‐based approach was employed to identify HBV integrations in tumour and para‐tumour tissues of PDAC. The biological functions of KMT2B were evaluated in PDAC cell lines as well as in subcutaneous and orthotopic mouse models of PDAC. Chromatin immunoprecipitation sequencing and RNA sequencing were used to identify the pathway involved in PDAC development.

HBV integration was detected in approximately one‐third of HBV DNA‐positive PDAC and adjacent para‐tumour tissues. A total of 425 viral‒host junctions were identified, with the majority located in intergenic regions (51.29%), followed by introns (43.29%) and exons (2.35%) of the human genome. Lysine methyltransferase 2B (KMT2B, also known as MLL4), a gene frequently targeted by HBV integration in hepatocellular carcinoma, was also found to be interrupted by HBV in PDAC. KMT2B was significantly upregulated in PDAC and promoted malignant behaviours both in vitro and in vivo. Mechanistically, KMT2B exerts its oncogenic effects by regulating the downstream target gene FYN through histone H3K4 trimethylation, leading to the activation of the PI3K/Akt signalling pathway.

HBV integration is a common event in HBV‐related PDAC and KMT2B has been identified as a novel PDAC‐related gene.

Hepatitis B virus (HBV) integrates in both tumour and adjacent para‐tumour tissues of pancreatic ductal adenocarcinoma (PDAC).
KMT2B, a target gene of HBV integration, promotes PDAC proliferation and metastasis in vivo and in vitro experiments.KMT2B exerts its oncogenic effects by regulating the downstream target gene FYN via histone H3K4 trimethylation, activating the PI3K/Akt signalling pathway.

Hepatitis B virus (HBV) integrates in both tumour and adjacent para‐tumour tissues of pancreatic ductal adenocarcinoma (PDAC).

KMT2B, a target gene of HBV integration, promotes PDAC proliferation and metastasis in vivo and in vitro experiments.

KMT2B exerts its oncogenic effects by regulating the downstream target gene FYN via histone H3K4 trimethylation, activating the PI3K/Akt signalling pathway.

HBV DNA integrates in multiple genes including KMT2B in pancreatic cancer. KMT2B upregulation caused by HBV integration or other mechanisms promotes FYN expression via histone H3K4 trimethylation at its promoter region. Increased FYN expression activates the PI3K/Akt signalling pathway, thus driving PDAC cell proliferation, migration and invasion.