GENOMIC IMPRINTING AND IGF2 INFLUENCE LIVER TUMORIGENESIS AND LOSS OFHETEROZYGOSITY IN SV40 T-ANTIGEN TRANSGENIC MICE

Maternal-specific loss of heterozygosity (LOH) and allelic imbalances [i.e., partial LOH (pLOH)] observed in SV40 T/t antigen-induced liver tumors suggests that an imprinted gene on chromosome 7 is involved in liver tumorigenesis, Maternal-specific LOH/pLOH may reflect the loss o f a maternally expressed tumor suppressor gene or the acquisition of p aternally active alleles of a growth promoter, In addition, two opposi tely imprinted genes on distal chromosome 7, Igf2 and H19, are re-expr essed in most liver tumors from an SV40 T/t antigen transgenic line (M 11T-G). Igf2 is a paternally expressed growth promoter, and H19 is a m aternally expressed gene that can suppress growth in some tumor cell l ines. We studied the role of Igf2 during Liver tumorigenesis by creati ng Igf2 (+/-) M11T-G mice. These mice are essentially null for Igf2 ex pression because imprinting normally precludes maternal Igf2 expressio n. M11T-G, Igf2 (+/-) males exhibit a 15-fold reduction in the frequen cy of large tumors. Igf2 (+/-) tumors do not express maternal lgf2, in dicating rigid imprinting control in the liver, LOH/pLOH analysis was performed on the tumors and indicates that acquisition of paternally a ctive Igf2 alleles is a major selective event for M11T-G liver tumorig enesis, This also implies the existence of an imprinted, maternally ex pressed tumor suppressor gene on chromosome 7 that is unlikely to be H 19.