Jang Jeong-Won, Kim Hye-Seon, Kim Jin-Seoub, Lee Soon-Kyu, Han Ji-Won, Sung Pil-Soo, Bae Si-Hyun, Choi Jong-Young, Yoon Seung-Kew, Han Dong-Jin, Kim Tae-Min, Roberts Lewis R
Division of Gastroenterology and Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea.
The Catholic University Liver Research Center, Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea.
Int J Mol Sci. 2021 Jun 30;22(13):7056. doi: 10.3390/ijms22137056.
Although hepatitis B virus (HBV) integration into the cellular genome is well known in HCC (hepatocellular carcinoma) patients, its biological role still remains uncertain. This study investigated the patterns of HBV integration and correlated them with (telomerase reverse transcriptase) alterations in paired tumor and non-tumor tissues. Compared to those in non-tumors, tumoral integrations occurred less frequently but with higher read counts and were more preferentially observed in genic regions with significant enrichment of integration into promoters. In HBV-related tumors, promoter was identified as the most frequent site (38.5% (10/26)) of HBV integration. promoter mutation was observed only in tumors (24.2% (8/33)), but not in non-tumors. Only 3.00% (34/1133) of HBV integration sites were shared between tumors and non-tumors. Within the HBV genome, HBV breakpoints were distributed preferentially in the 3' end of HBx, with more tumoral integrations detected in the preS/S region. The major genes that were recurrently affected by HBV integration included and for tumors and for non-tumors. Functional enrichment analysis of tumoral genes with integrations showed enrichment of cancer-associated genes. The patterns and functions of HBV integration are distinct between tumors and non-tumors. Tumoral integration is often enriched into both human-virus regions with oncogenic regulatory function. The characteristic genomic features of HBV integration together with alteration may dysregulate the affected gene function, thereby contributing to hepatocarcinogenesis.
尽管乙型肝炎病毒（HBV）整合到细胞基因组在肝癌（HCC）患者中已广为人知，但其生物学作用仍不明确。本研究调查了HBV整合模式，并将其与配对的肿瘤组织和非肿瘤组织中的端粒酶逆转录酶（TERT）改变相关联。与非肿瘤组织相比，肿瘤组织中的整合发生频率较低，但读数较高，并且更优先在基因区域观察到，启动子区域的整合显著富集。在HBV相关肿瘤中，TERT启动子被确定为HBV整合最常见的位点（38.5%（10/26））。TERT启动子突变仅在肿瘤组织中观察到（24.2%（8/33）），而在非肿瘤组织中未观察到。肿瘤组织和非肿瘤组织之间仅3.00%（34/1133）的HBV整合位点相同。在HBV基因组内，HBV断点优先分布在HBx的3'端，在preS/S区域检测到更多的肿瘤整合。受HBV整合反复影响的主要基因在肿瘤组织中包括TERT和CCND1，在非肿瘤组织中为MLL4。对具有整合的肿瘤基因进行功能富集分析显示癌症相关基因富集。肿瘤组织和非肿瘤组织中HBV整合的模式和功能不同。肿瘤整合通常富集到具有致癌调节功能的人-病毒区域。HBV整合的特征性基因组特征与TERT改变可能会失调受影响的基因功能，从而促进肝癌发生。
