Poster 2
Presenter: Andrea Bilger
Thursday, 4:00 – 6:00pm

Identification of the Ifi202b candidate liver cancer modifier by linkage, microarray, and CGH analysis

Andrea Bilger and Norman Drinkwater
University of Wisconsin-Madison

The mouse Hcs7 liver cancer susceptibility locus on distal Chr 1 differentially affects tumor growth in the susceptible C3H/HeJ (C3H) and resistant C57BL/6J (B6) strains. The C3H allele of Hcs7 confers an approximately five-fold increased susceptibility to carcinogen-induced HCC, as well as increased susceptibility to spontaneous HCC. Hcs7 does not appear to affect apoptosis or mitosis during initiation, but by 16 weeks preneoplastic lesions in mice carrying the C3H allele are 3.4-fold larger than those in B6. Hcs7 maps to a 3.3 Mb region that carries 44 genes, of which many respond to immune stimuli.

We have identified a strong candidate for the Hcs7 susceptibility locus: the interferon-inducible gene Ifi202b. Ifi202b is upregulated by androgen and downregulated by estrogen, as is susceptibility to HCC. The Hcs7 locus, including Ifi202b, is orthologous to parts of human chromosome 1q23 and 1q43 that are amplified in ~70% of human liver tumors. Human IFI16 is a candidate for the human susceptibility locus: its transcripts closely resemble those of Ifi202b, it is upregulated by androgen, and it is expressed in growing liver cells.

Ifi202b expression in the liver is 50-fold higher in the C3H strain (by microarray and qRTPCR) than in the B6 strain. The CBA/J strain, also highly susceptible to liver tumorigenesis due to a locus on distal Chr 1, likewise expresses high levels of Ifi202b. Importantly, a de novo mutation in Ifi202b in a B6.C3H congenic line correlates with this line's unexpected resistance to HCC and with a 50% reduction in Ifi202b expression.