Genome-wide SNP analysis of Tg.AC transgenic mice reveals an oncogenic collaboration between v-Ha-ras and Ink4a, which is absent in p53 deficiency

Abstract

Oncogenesis is a progressive process often involving collaboration between various oncogenes and tumor suppressors. To identify those genes that collaborate with oncogenic ras, we took advantage of the Tg.AC transgenic mouse, a line that harbors the v-Ha-ras transgene and spontaneously develops an array of malignant tumors. By crossing Tg.AC mice on an inbred FVB background to other inbred strains, F1 mice were created that could be analysed using genome wide, single nucleotide polymorphism (SNP) screens. Loss of heterozygosity (LOH) in tumors and tumor cell lines marked a somatic event, possibly the inactivation of tumor suppressor gene(s). LOH could also represent DNA damage, a sign of genomic instability in the pretransformed cell. Nonetheless, the screens showed no evidence of such generalized genomic instability. Instead, they revealed a single region of LOH on chromosome 4 that occurred via somatic recombination/gene conversion, generating a region of isoparental disomy. This LOH provided a clue that linked v-Ha-ras to the inactivation of the Ink4a locus in 25 of 32 tumor cell lines. This collaboration is seen regardless of tumor type or genetic background. In contrast, tumors that develop in bitransgenic mice bearing both the v-Ha-ras gene and a heterozygous mutant p53 allele tend to retain the Ink4a locus and instead lose the p53 wild-type allele. This suggests that different strategies can be selected to collaborate with v-Ha-ras in tumorigenesis.

PIG11 is Involved in Hepatocellular Carcinogenesis and Its Over-expression Promotes Hepg2 Cell Apoptosis

“…The results were consistent with the common observation that the protein expression of tumour suppressor genes, such as p53 and p16, are usually lost or down-regulated in malignant tumours [12,13]. This suggested that the PIG11 gene was a candidate liver tumour suppressor gene and was involved in tumourigenesis and development of hepatocarcinoma.…”