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Kay
01-15-2009, 04:46 AM
UCSF researchers have used a new strategy to study inherited susceptibility for skin cancer in mice. In the process, they have identified a network of genes that may play a key role in controlling this susceptibility. The technique, the scientists say, could be used to identify such genes in human cancers.

UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care.


The finding, reported in the Jan. 11, 2009 Advance Online Publication of Nature, builds on a promising technique called genetic network analysis, which allows scientists to analyze complex systems. The technique has been used to study heritable traits such as obesity and to study the workings of organs such as the human brain. However, it has never been used in cancer genetics, due to the complexity in studying how genetic differences influence whether an organism will develop cancer.

"This is the first time these techniques have been used to analyze cancer susceptibility. Using this framework, these methods should be applicable in many different areas of cancer research or other types of heritable diseases that thus far have been difficult to study," says senior study author Allan Balmain, PhD, UCSF professor of biochemistry and Barbara Bass Bakar Distinguished Professor in Cancer Genetics at the UCSF Helen Diller Family Comprehensive Cancer Center.

Genetic network analysis produces a map of how key genes interact with each other to control physiological functions and structures. Applying this tool to cancer research opens a new window on the disease.

"There are rare mutations that strongly predispose people to getting a type of cancer, but most cancers are caused by a combination of environmental influences and moderately influential differences in the DNA that an individual is born with. The kinds of changes we are studying are not instant tickets to cancer but are predispositions. This is something that is much harder to track but could be very useful in the future realm of personalized medicine," says David Quigley, MA, the first author on the paper and the lead computational expert on the project.

Significantly, the UCSF researchers used only a personal computer to map out the relevant gene networks. Previous studies using this technique have required supercomputers or other forms of high-powered computing. Reducing computing requirements should allow many more laboratories to use genetic network analysis techniques.

In their study, the researchers bred together laboratory mice of the species Mus Musculus with wild mice of the species Mus Spretus. M. Musculus has strong susceptibility to skin cancer and M. Spretus has strong resistance to skin cancer.

The researchers attempted to induce skin cancer in the mixed offspring of these mice and then examined how genetic control of gene expression affected their tumor susceptibility. By examining genetic differences between mice who did and did not develop skin cancer, the researchers identified the Vitamin D Receptor as a candidate master regulator for skin cancer in the mice.

Vitamin D levels in the blood have long been recognized as having an influence on skin functions and susceptibility to inflammatory diseases in humans and mice. Diminished Vitamin D levels or a faulty Vitamin D Receptor gene have also been associated with the propensity for various types of cancer in people and mice.

"Now we have shown Vdr can be linked to skin cancer in mice using genetic network analysis methods," says Balmain. Because man and mouse share significant similarities in cancer genetics and cancer development, he says, gene candidates for cancer in mice could directly translate into gene candidates for cancer susceptibility in humans.

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