Jefferson Researchers Find Altered Gene in Several Different Types of Common Cancers

A team of Jefferson Medical College investigators, led by Kay Huebner, PhD, professor of microbiology and immunology at Jefferson's Kimmel Cancer Center, and Carlo M. Croce, MD, director of the Kimmel Cancer Center, have identified and characterized a gene named FHIT that, when abnormal, leads to several types of cancer. The research appears in the February 23, 1996 issue of Cell.

FHIT is involved in a variety of airway and digestive tract tumors

The investigators found that the FHIT gene, located in a fragile area of the human chromosome 3 known as 3p14.2, is involved in a variety of airway and digestive tract tumors, such as nasopharyngeal, esophageal, stomach and colorectal carcinomas. It seems likely that FHIT also may be involved in kidney, lung, ovarian, cervical and breast cancers. Testing of tissues from these types of cancer for abnormal FHIT is in progress.

In the study, the investigators examined normal and cancerous tissues obtained immediately after surgery from esophageal, colon and stomach cancer patients. Other tissues studied were obtained in the form of cultured cell lines.

Abnormal FHIT is associated with chromosomal deletions leading to loss of FHIT gene function. A common characteristic of the types of tumors that exhibit abnormal FHIT genes is that they arise from epithelial cell linings that are commonly exposed directly to environmental carcinogens. It is possible that exposure to agents that interfere with DNA replication, such as nicotine, caffeine, alcohol and known carcinogens, may lead directly to alterations in the FHIT gene and the inability to produce a normal FHIT protein, which may then lead to tumorigenesis.

FHIT discovery may lead to new drugs

Drs. Huebner and Croce indicate that the discovery of the FHIT gene may lead not only to the identification of individuals predisposed to some of the most common human cancers, but also to the development of new drugs that may arrest the growth of cancer cells. The discovery of the mechanisms involved in causing FHIT abnormalities could one day lead to prevention of some of the most common human cancers.

"We know the FHIT gene is altered in airway and digestive tract cancers, and we're pretty sure we'll find it altered in other important types of cancer," said Dr. Huebner. "Since the FHIT gene makes a small protein, probably an enzyme, the protein itself will provide clues to the discovery of therapeutic drugs."

Jefferson's Masataka Ohta, PhD, the first author of the study, expressed hope that understanding of FHIT gene abnormalities will help in the fight against esophageal cancer, which is especially prevalent in Japan.

FHIT is a significant development in cancer medicine

Robert L. Comis, MD, director of clinical programs at Jefferson's Kimmel Cancer Center and chair of the Eastern Clinical Oncology Group (ECOG), says, "This work is a very significant development in the world of cancer medicine for several reasons. First, FHIT is a major tumor-suppresser gene found in a region (3p) that researchers worldwide have been working on for a long time. Second, FHIT is involved with a host of different cancers ­p; some of the most common human malignancies. Finally, it is probable that abnormal FHIT could be inherited. With this knowledge, we will be able to test for abnormal FHIT to see whether certain patients have a predisposition to a variety of cancers."

The normal protein produced by FHIT, Fhit, is very similar to a yeast enzyme protein that was isolated in the laboratory of Larry Barnes, PhD, at the University of Texas, San Antonio. The similarity to the yeast enzyme, the researchers believe, will help them to understand how the abnormal FHIT gene contributes to cancer growth, illustrating the strong interdependence of human genetics and genetics of distantly related organisms.

The Jefferson team's work grew from cancer research that started in 1979, when it was observed that an Italian-American family, which had several members with renal carcinoma, was transmitting a chromosome translocation in the 3p14.2 region of their chromosomes. This same region was later found to be involved with many other cancer types. At the time, it was suggested that the translocation was affecting the expression of an unknown tumor-suppresser gene, thus leading to cancer.

Another clue was provided by Nicolai Lisitsyn, PhD, and colleagues, with Michael Wigler, PhD, of Cold Spring Harbor Laboratory, Long Island, who discovered a fragment of chromosome 3 that was altered in colon tumors. When the Jefferson team determined that this fragment was from region 3p14.2, they intensified their search for a gene in that region.

The Jefferson work also grew out of DNA research done in the 1980s that speculated that fragile sites of the human chromosome are less stable and may lead to cancer. These sites resemble gaps and breaks, suggesting that they could be the location of chromosomal rearrangements in cancer. Abnormal FHIT is marked by such gaps and breaks within its sequence.

Since zinc deficiency may cause proliferation of the epithelial cells lining the esophagus, and is associated with a high frequency of esophageal tumors in man and rats, the Jefferson researchers also have suggested that zinc deficiency may mimic the loss of the FHIT protein, thus leading to cancer.