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Jefferson Scientists Find New Link Between Gene And Hereditary Colon Cancer

Date:
April 26, 2000
Source:
Jefferson Medical College
Summary:
The evidence is mounting against the FHIT gene. Located in the genome’s most fragile region on chromosome 3, FHIT, when damaged, has already been implicated in contributing to a number of cancers, such as esophageal, gastric, kidney, breast and lung. Now, researchers at Jefferson Medical College have unexpectedly found evidence indicating that FHIT may also play a role in a common form of hereditary colorectal cancer.

The evidence is mounting against the FHIT gene. Located in the genome’s most fragile region on chromosome 3, FHIT, when damaged, has already been implicated in contributing to a number of cancers, such as esophageal, gastric, kidney, breast and lung.

Now, researchers at Jefferson Medical College have unexpectedly found evidence indicating that FHIT may also play a role in a common form of hereditary colorectal cancer. The finding may help scientists better understand the mechanisms of such cancers. The scientists report their findings April 25 in the Proceedings of the National Academy of Sciences.

Researchers, led by Kay Huebner, PhD, professor of microbiology and immunology at Thomas Jefferson University and a member of Jefferson’s Kimmel Cancer Center, set out to study genetically altered mice lacking FHIT. They gave the mice carcinogens to see if they were sensitive to genetic damage from the cancer-causing substances. They found they were, says Dr. Huebner, "providing evidence that the gene is a so-called gatekeeper that helps prevent carcinogen-caused tumors."

But they noticed that mice with damaged versions of FHIT also developed odd sebaceous gland tumors, similar to those found in patients with Muir-Torre familial cancer syndrome. Most such cases have been linked to a defect in a system to fix genetic mistakes, called mismatch repair. This defect is also associated with hereditary nonpolyposis colon cancer (HNPCC).

"We were excited because the same gene in Muir-Torre syndrome is likely affected as in HNPCC," Dr. Huebner says. "In Muir-Torre syndrome, patients get one or more sebaceous and visceral tumors. It is a subset of HNPCC.

"In these mice, which don't show a mismatch repair defect, loss of FHIT contributes to an HNPCC-like disease," she explains. Seven of 12 mice lacking one copy of the FHIT gene had sebaceous tumors, while none of the control mice, which had two working copies of the FHIT gene, developed these tumors. Additionally, 100 percent of mice lacking one copy of FHIT developed gastric cancers after carcinogen exposure, while only 25 percent of mice with both copies of FHIT developed such tumors.

Dr. Huebner believes that in a certain percentage of HNPCC cases, both copies of FHIT become inactivated after mismatch repair genes are lost. Such repair genes may be important for maintaining the integrity of the FHIT gene on the chromosome.

"This suggests that somehow, loss of mismatch repair function also results in either increased damage to the FHIT fragile locus, or in some other way, it affects expression of the FHIT gene," she says.

Understanding FHIT's role in preventing the cancer-causing effects of a carcinogen may be paramount if researchers are going to develop ways to treat or prevent disease. In 1996, Dr. Huebner, in collaboration with Carlo M. Croce, MD, director of the Kimmel Cancer Center and professor and chair of microbiology and immunology at Jefferson Medical College, identified and characterized FHIT. The investigators found that the FHIT gene is located in the human genome’s most fragile area. The area is likely to have DNA gaps, breaks and rearrangements. They have been working to find out if FHIT’s fragility is involved in the start or progression of cancers.

"We knew this [FHIT] site was prone to damage by carcinogens," Dr. Huebner says. "We know some of the carcinogens that can damage FHIT and some of the kinds of damage that can occur within FHIT for some cancers."

To find out if the FHIT gene was indeed protective against carcinogens, they created "knockout" mice, or animals lacking one or both copies of the FHIT gene. They could then test to see if the FHIT locus was susceptible to carcinogens. "We hypothesized that one of the reasons FHIT gene was so frequently lost in cancer was that it has a fragile region and damage to fragile sites can be caused by carcinogens," she explains.

They compared mice that were missing one FHIT gene copy, or "plus/minus" mice, to normal, or "plus/plus" mice. Each was exposed to nitrosomethylbenzylamine, a carcinogen. Ten weeks after the treatmentwas completed, they found that 100 percent (12 of 12) of the plus/minus mice had tumors, mainly in the stomach, and only 25 percent (two of eight) of the normal plus/plus mice had such tumors.

"Since the only difference between these mice is that the plus/minus mice are missing one FHIT gene," Dr. Huebner says, "the absence of that allele had to have been an initiating cause of those tumors. It demonstrates absolutely that the FHIT locus is sensitive to carcinogen damage," which had not been proven before. "That extra FHIT allele is protective against tumors."

One of the scientists’ next steps is to continue to study FHIT's role in cancer initiation by inducing tumors in mice and then attempting to prevent or cure them by using engineered viruses containing FHIT.


Story Source:

The above story is based on materials provided by Jefferson Medical College. Note: Materials may be edited for content and length.


Cite This Page:

Jefferson Medical College. "Jefferson Scientists Find New Link Between Gene And Hereditary Colon Cancer." ScienceDaily. ScienceDaily, 26 April 2000. <www.sciencedaily.com/releases/2000/04/000426075807.htm>.
Jefferson Medical College. (2000, April 26). Jefferson Scientists Find New Link Between Gene And Hereditary Colon Cancer. ScienceDaily. Retrieved July 31, 2014 from www.sciencedaily.com/releases/2000/04/000426075807.htm
Jefferson Medical College. "Jefferson Scientists Find New Link Between Gene And Hereditary Colon Cancer." ScienceDaily. www.sciencedaily.com/releases/2000/04/000426075807.htm (accessed July 31, 2014).

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