title: Identification of HBV-MLL4 Integration and Its Molecular Basis in Chinese Hepatocellular Carcinoma.
abstract: To gain molecular insights of HBV integration that may contribute to HCC tumorigenesis, we performed whole transcriptome sequencing and whole genome copy number profiling of hepatocellular carcinoma (HCC) samples from 50 Chinese patients. We identified a total of 33 HBV-human integration sites in 16 of 44 HBV-positive HCC tissues, which were enriched in HBV genotype C-infected patients. In addition, significantly recurrent HBV-MLL4 integration (18%; 8/44) was found in this cohort of patients. Using long-range PCR and Sanger sequencing, we comprehensively characterized gDNA and cDNA sequences that encode for the HBV-MLL4 transcripts, and we revealed that HBV integration into MLL4 exons led to much higher mRNA expression of MLL4 than the integration into MLL4 introns due to an alternative splicing mechanism. Moreover, the HBV-MLL4 integration occurred almost exclusively in CTNNB1 and TP53 wild-type patients. The integration was also associated with a distinct gene expression profile. In conclusion, this is the first report on the molecular basis of the MLL4 integration driving MLL4 over-expression. HBV-MLL4 integration occurred frequently in Chinese HCC patients, representing a unique molecular segment for HCC with HBV infection.
authors.affiliation: AstraZeneca Asian and Emerging market iMed, Zhangjiang Hi-Tech Park, Shanghai, P. R. China.
authors.forename: Hua
authors.initials: H
authors.lastname: Dong
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, Shanghai, P. R. China.
authors.forename: Lan
authors.initials: L
authors.lastname: Zhang
authors.affiliation: AstraZeneca Asian and Emerging market iMed, Zhangjiang Hi-Tech Park, Shanghai, P. R. China.
authors.forename: Ziliang
authors.initials: Z
authors.lastname: Qian
authors.affiliation: AstraZeneca Asian and Emerging market iMed, Zhangjiang Hi-Tech Park, Shanghai, P. R. China.
authors.forename: Xuehua
authors.initials: X
authors.lastname: Zhu
authors.affiliation: AstraZeneca Asian and Emerging market iMed, Zhangjiang Hi-Tech Park, Shanghai, P. R. China.
authors.forename: Guanshan
authors.initials: G
authors.lastname: Zhu
authors.affiliation: R&D Information, AstraZeneca, Shanghai, P. R. China.
authors.forename: Yunqin
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, Shanghai, P. R. China.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Xie
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, Shanghai, P. R. China.
authors.forename: Qinghai
authors.initials: Q
authors.lastname: Ye
authors.affiliation: AstraZeneca Asian and Emerging market iMed, Zhangjiang Hi-Tech Park, Shanghai, P. R. China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zang
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, Shanghai, P. R. China.
authors.forename: Zhenggang
authors.initials: Z
authors.lastname: Ren
authors.affiliation: AstraZeneca Asian and Emerging market iMed, Zhangjiang Hi-Tech Park, Shanghai, P. R. China.
authors.forename: Qunsheng
authors.initials: Q
authors.lastname: Ji
mesh_terms: D017398:Alternative Splicing; D044466:Asian People / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000821:virology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human / Q000235:genetics; D005838:Genotype; D006515:Hepatitis B virus / Q000502:physiology*; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000821:virology*; D014158:Transcription, Genetic; D016662:Virus Integration
chemical_list: D004268:DNA-Binding Proteins; D011495:Histone-Lysine N-Methyltransferase; C530816:MLL4 protein, human