title: Integration of hepatitis B virus DNA into the myeloid/lymphoid or mixed-lineage leukemia (MLL4) gene and rearrangements of MLL4 in human hepatocellular carcinoma.
abstract: Integration of hepatitis B virus (HBV) DNA into host DNA is detected in about 90% of HBV-related hepatocellular carcinoma (HCC), but the preferential sites of the viral integration etiologically relevant to oncogenesis have been controversial. By using an adaptor-ligation/suppression-PCR, we identified four integrations into the myeloid/lymphoid or mixed-lineage leukemia 4 (MLL4) gene from 10 HCC patients with positive HBV surface antigen (HBsAg). Determination of the cellular-virus DNA junction demonstrated that various lengths of the virus were integrated within 300 bp of intron 3 flanked by the Alu element of MLL4. Chimeric hepatitis B virus X gene (HBx)/MLL4 transcripts and the HBx fusion proteins were detected. DNA microarray revealed that HBx/MLL4 fusion proteins suppressed unique genes in HepG2 cells. Finally, chromosomal translocations of intron 3 of MLL4 to the specific region of chromosome 17p11.2 in 22 out of 32 HCC patients were observed, showing that the intron 3 region of MLL4 gene would be a target of translocation breakpoint. In conclusion, the present data suggest that the translocation breakpoint of MLL4 gene is one of the preferential targets for HBV DNA integration into the MLL4 gene and the HBV DNA integration may be involved in liver oncogenesis.
authors.affiliation: Second Department of Surgery, School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Saigo
authors.forename: Kenichi
authors.initials: K
authors.lastname: Yoshida
authors.forename: Ryuji
authors.initials: R
authors.lastname: Ikeda
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Sakamoto
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Murakami
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Urashima
authors.forename: Takehide
authors.initials: T
authors.lastname: Asano
authors.forename: Takashi
authors.initials: T
authors.lastname: Kenmochi
authors.forename: Ituro
authors.initials: I
authors.lastname: Inoue
mesh_terms: D001483:Base Sequence; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000821:virology*; D002886:Chromosomes, Human, Pair 17; D004279:DNA, Viral / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D006515:Hepatitis B virus / Q000235:genetics*; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000821:virology*; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D014178:Translocation, Genetic; D016662:Virus Integration
chemical_list: D004279:DNA, Viral; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D011495:Histone-Lysine N-Methyltransferase; C530816:MLL4 protein, human