Jefferson Researchers Find Altered Gene in Several Different Types of
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.