Scientists Identify Potential Lung Tumor Susceptibility Genes in Mice

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Michael C. Purdy
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Oct. 28, 2003 – Researchers at Washington University School of Medicine in St. Louis have tentatively linked two mouse genes, lung adenoma susceptibility gene 1 (Las-1) and Kirstin rat sarcoma oncogene 2 (Kras2), to increased creation and growth of lung tumor cells, a finding that may aid the search for genes with similar effects in humans.

"Most people regard lung cancer in humans as something primarily caused by tobacco smoke," says Ming You, MD, PhD, professor of surgery and a researcher at the Siteman Cancer Center. "But there is epidemiological evidence implying that even among heavy smokers a genetic component puts some people more at risk for lung cancer than others."

The results, developed in conjunction with a research group at the University of Michigan in Ann Arbor, are to be published in the October 28 Proceedings of the National Academy of Sciences. According to You, the findings are the first major advance in 10 years in the search for lung tumor susceptibility genes in mouse models or humans. Researchers have already identified genes in human DNA similar to the mouse genes.

Lung cancers kill more patients than any other cancer, and their high and rapid mortality rates make it challenging to gather blood samples for studies of the genetics of human lung cancer susceptibility, You says. When researchers began modeling the disease in mice more than a half- century ago, they found a wide spectrum of susceptibility: Most types of mice are highly resistant to lung tumors, but a minority can develop lung tumors when exposed to carcinogens, and a few can even develop spontaneous lung tumors.

To identify susceptibility genes, researchers in You's laboratory repeatedly crossbred a strain of mice with maximum resistance to lung cancer and a strain of mice highly susceptible to lung cancer. They tested reactions of each of the resulting mouse strains to carcinogens and began searching DNA from those that developed the most tumors.

Previous studies had linked lung tumor susceptibility to a region on mouse chromosome 6; with data from their new lines of mice, You's group was able to focus the search on a smaller area within that region.

"This section has about 12 genes, but only four of them have amino acid polymorphisms — changes in the DNA that could potentially change the function of the protein produced from the gene," You says.

Researchers took copies of the four genes from the mouse strains and inserted them in cell lines used to test cell growth, comparing the effects of genes from cancer-susceptible mice with the effects of genes from cancer-resistant mice. Only one gene produced a difference in the tests, a gene that You's group named Las-1. Cells with Las-1 from cancer-susceptible mice had high rates of cell division and growth, but cells given the same gene from cancer-resistant mice were normal.

Next, researchers took the cell lines and grafted them onto the backs of live mice. Grafts carrying the Las-1 gene from susceptible mice became large tumors in a few weeks, while grafts with the gene from the resistant mice grew very little.

Another gene in the search area on mouse chromosome 6 caught the scientists' eyes: Kras2, a proto-oncogene previously linked to cancer development. The were no significant changes in the regions of the Kras2 gene that code for protein parts, but other areas of DNA that affect how often the gene's protein is made did have changes.

To test how differences in levels of the protein made from the Kras2 gene might affect tumor susceptibility, You's group deleted one copy of the gene in a strain of mice, halving the ability of the mice's cells to make the protein. They then bred that strain with mice with the high susceptibility and high resistance forms of Kras2, producing two new strains of mice. Both strains were missing a copy of Kras2, but one had a copy of the cancer-resistant Kras2 gene, and one had a copy of the cancer-susceptible Kras2 gene.

When exposed to carcinogens, the new mice strains developed many more tumors than normal mice. Researchers next compared the tumors in the two experimental strains and found little difference in the number of tumor cells. However, the tumor cells were much bigger in size in mice with the cancer-susceptible form of Kras2, suggesting that Kras2 primarily regulates the cancer cells' ability to grow.

You is currently investigating the relationship between Las-1 and Kras2 on a number of different fronts, including studies of mice with both genes disabled at birth, a test that he calls the "more definitive proof" of the links between the genes and lung cancer susceptibility.

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Zhang Z, Futamura M, Vikis HG, Wang M, Li J, Wang Y, Guan K-L, You M. Positional cloning of the major quantitative trait locus underlying tumor susceptibility in mice. Proceedings of the National Academy of the Sciences, October 28, 2003.

Funding from the National Institutes of Health.

The full-time and volunteer faculty of Washington University School of Medicine are the physicians and surgeons of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.


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