Getting a Jump on Cancer Genetics

Scientists using 'jumping genes' to uncover tumor-linked mutations

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HealthDay Reporter

FRIDAY, July 15, 2005 (HealthDay News) -- Trying to stop cancer before it starts, researchers have developed a new method of spotting tumor-causing genes in mice -- offering hope for better early detection in humans.

The detection process relies on the use of so-called "jumping genes" -- pieces of mobile DNA called transposons found in humans, animals and fish. These DNA fragments can enter or move around an organism's fixed genes, disabling or jump-starting normal genetic function.

The research was conducted by two teams of scientists at the University of Minnesota Cancer Center (UMCC) in Minneapolis and the National Cancer Institute (NCI). In each study, researchers used the jumping gene mechanism to force hidden cancer-related genes to reveal themselves.

"We know of about 300 cancer-causing genes, but I suspect there are more like 30,000 of them," said David A. Largaespada, an associate professor at UMCC and a co-author of both studies. "But finding them is like finding a needle in a haystack. So we figured out a quicker, more accurate and more efficient way to find these genes. And hopefully what we learn in mice will be analogous to what we will find among humans."

In the July 14 issue of Nature, Largaespada and his colleagues report on their work with a fish-derived jumping DNA, designed specifically for their cancer research. The DNA was named "Sleeping Beauty" to describe transposons that had been reactivated by the scientists after having lost their natural jumping ability over time.

In one study -- led by the UMCC team -- Sleeping Beauty was hard-wired into the DNA of a group of 26 1-year-old genetically altered mice, all specifically bred for the cancer experiments.

The Sleeping Beauty DNA fragments were then tracked as they set off jumping about a particular mouse's genetic structure, or genome.

Aiming to read genome's fine print faster and more accurately, Largaespada and his colleagues relied on the Sleeping Beauty's ability to cause gene mutation upon contact.

If the Sleeping Beauty DNA hopped directly inside a mouse gene, it would prevent the gene from functioning normally. On the other hand, when the jumping DNA hopped to a nearby location -- but remained outside the gene -- it would provoke gene activity.

While not all the affected mouse genes were revealed as having a relationship to cancer, this mutation experiment enabled the researchers to identify specific genes that appeared to either offer protection from, or promotion of, cancer in the mice.

For example, if cancer tumors grew as a result of a certain gene's impaired functioning, then that gene was tagged as protective against cancer. On the other hand, if cancer tumors grew as a result of a certain gene's activity, then that gene was tagged as cancer-causing.

Furthermore, the researchers were able to analyze malignant tumors that formed as a direct result of Sleeping Beauty exposure -- isolating and mapping the on-off cancer role of specific genes in each tumor.

In a similar vein, the second study -- led by the NCI team -- focused specifically on the ability of the Sleeping Beauty-jumping cell method to help scientists map genes causing lymphoma, a cancer of the immune system.

While acknowledging that there is a leap to be made moving from mice to human cancer patients, both research teams touted the success and potential of the jumping gene cancer screening method.

Since many of the mutated genes that cause cancer in mice often cause cancer in humans, they also suggested that success in identifying previously unknown cancer-causing genes among mice could lead to a more detailed portrait of cancer genetics in humans.

"If you look at the data carefully, we do find that there are also a bunch of new genes in mice that cause cancer that aren't already known to be involved in human cancer development," said Largaespada. "And that gives us a clue to look for more cancer genes in humans -- that there's more to discover."

Largaespada said future work at UMCC will focus on using the jumping gene screening method to compile a list of cells that lead to colon cancer, lung cancer, prostate cancer and myeloid leukemia. The team at NCI will focus on breast cancer, brain cancer and melanoma.

"We need to know this information as soon as possible, because the drug companies need to know what to target when they're looking to develop new treatments for different cancers," he said. "It will take a lot of hard work and time, but this technology is one additional tool that researchers will have to meet that goal."

Dr. Carlo M. Croce, chairman of the department of molecular virology, immunology and medical genetics at Ohio State University, shares the hope that jumping gene research will contribute to cancer treatment.

"This is a novel method to look at genes that might be activated and contribute to cancer," said Croce. "It's not a revolutionary step, but it's a step forward. These are two interesting studies, and the people who have done this work are very good geneticists. So I think it will have a wide application, and it might be an improvement over already established screening approaches."

More information

For more on cancer genetics, check out the National Cancer Institute.

SOURCES: David A. Largaespada, PhD, associate professor, Cancer Center, University of Minnesota, Minneapolis; Carlo M. Croce, MD, chairman, department of molecular virology, immunology and medical genetics, Ohio State University, and director, human cancer genetics program, Ohio State University Cancer Center, Columbus; July 14, 2005, Nature

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