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Updated: Jul 9, 2026
Mosaic Zebrafish Transgenesis for Functional Genomic Analysis of Candidate Cooperative Genes in Tumor Pathogenesis
Published on: March 31, 2015
Genome-wide SNP analysis of Tg.AC transgenic mice reveals an oncogenic collaboration between v-Ha-ras and Ink4a,
1Department of Genetics, Harvard Medical School, Boston, MA 021115, USA.
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.
Insights
Oncogenic ras collaborates with tumor suppressors during cancer development. Researchers found that v-Ha-ras inactivation of the Ink4a locus is a common strategy in tumor formation.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Oncogenesis involves the interplay between oncogenes and tumor suppressor genes.
- The Tg.AC transgenic mouse model, which expresses the v-Ha-ras oncogene, spontaneously develops tumors, making it suitable for studying oncogene collaboration.
Purpose of the Study:
- To identify genes that collaborate with the oncogenic v-Ha-ras transgene.
- To investigate the mechanisms by which v-Ha-ras contributes to tumorigenesis in the Tg.AC mouse model.
Main Methods:
- Genome-wide single nucleotide polymorphism (SNP) screening was employed on F1 mice derived from crossing Tg.AC mice with other inbred strains.
- Loss of heterozygosity (LOH) analysis was performed on tumors and tumor cell lines to identify potential tumor suppressor gene inactivation events.
- Specific genetic loci, including Ink4a and p53, were analyzed in relation to v-Ha-ras expression and tumor development.
Main Results:
- A specific region of LOH on chromosome 4, resulting in isoparental disomy, was identified in tumors.
- This LOH was linked to the inactivation of the Ink4a locus in a significant proportion (25/32) of tumor cell lines, irrespective of tumor type or genetic background.
- Tumors co-expressing v-Ha-ras and a mutant p53 allele tended to retain Ink4a but lose the wild-type p53 allele, indicating alternative collaborative strategies.
Conclusions:
- The Ink4a tumor suppressor locus is frequently inactivated in collaboration with the v-Ha-ras oncogene during tumorigenesis.
- Tumorigenesis driven by v-Ha-ras can involve distinct genetic pathways, either targeting Ink4a or p53, depending on the genetic context.
- These findings highlight the complex genetic collaborations that drive oncogenesis and offer insights into potential therapeutic strategies.
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