Jefferson Study Points to Altered FHIT Gene As Important Cause of Different
Researchers at Jefferson's Kimmel Cancer Center, in collaboration
with investigators at Italy's National Cancer Institute of Milan led by
Marco Pierotti, PhD, have found abnormalities in the FHIT gene in both small
cell and nonsmall cell lung cancer. The high percentage of tumors with abnormal
FHIT suggests that the gene plays a critical role in lung cancer development,
and underscores the importance of the discovery of this new cancer gene
by Jefferson researchers just a few months ago.
Of the 14 tumors and three cell lines of small cell lung cancer studied,
80 percent exhibited abnormal FHIT. Of the 45 non-small cell lung cancer
tumors studied, 40 percent exhibited abnormal FHIT. Also, approximately
80 percent of all lung tumors had a loss of one FHIT allele, which is observed
in pairs in healthy cells. These results appear in the April 5, 1996 issue
of the journal Cell.
Breakthrough may provide important cancer prevention clues.
"This is a breakthrough in our understanding of the initial steps involved
in the pathogenesis of lung cancer and may provide important clues for cancer
prevention. This study indicates that the FHIT gene is the target for genetic
alterations caused by smoking," says Carlo M. Croce, MD, director of
the Kimmel Cancer Center of Jefferson Medical College and a senior author
of the study.
"The FHIT gene is located in a fragile area of human chromosome 3 at
band 3p14. Since the fragile area (FRA3B) was discovered, it has been linked
to esophageal, colon and stomach cancer. This is the first study to examine
the occurrence of abnormalities of FHIT in DNA samples of lung cancer,"
says Kay Huebner, PhD, also a senior author of the study.
It is possible that exposure to agents that interfere with DNA replication
and other known carcinogens, such as benzopyrene present in cigarette smoke,
may lead directly to alterations in the FHIT gene and the inability to produce
a normal FHIT protein; this may then lead to tumorigenesis by either stimulating
the proliferation of the cells that are the precursors of cancer or by causing
A common characteristic of the types of tumors that exhibit abnormal FHIT
is that they arise from epithelial cell linings. Such cells are commonly
exposed directly to environmental carcinogens.
Inherited alterations in FHIT may predispose people and families to lung,
kidney, digestive track and other types of cancer. A study is under way
at Jefferson that will determine if some individuals are more susceptible
to FHIT gene abnormalities. These patients will then be able to adapt their
lifestyles accordingly so that they could minimize exposure to carcinogens.
In the long run the Jefferson researchers hope to better understand the
molecular mechanisms involved in causing FHIT abnormalities and therefore
to be able to develop new drugs that may arrest the growth of cancer cells.
Understanding of the molecular pathogenesis of the lung cancer may help
to prevent it and provide new and more sensitive means to better diagnose
and treat lung cancer patients. Lung cancer is a major cause of mortality
worldwide, and the overall survival rate has not improved significantly
in the last 20 years.
FHIT operation may prove easier to study than other cancer-causing genes.
Previous work by the same Jefferson researchers that appeared in the February
23, 1996 issue of Cell suggests that the way FHIT operates in cells may
be studied more easily than some other cancer-causing genes, since the normal
protein produced by FHIT, FHIT, is very similar to a yeast enzyme that was
isolated in the laboratory of Larry Barnes, PhD, at the University of Texas,
San Antonio, and can now be easily observed in the laboratory.
Testing of kidney, ovarian, cervical and breast cancers for abnormal FHIT
is in progress at the Kimmel Cancer Center. Gabriella Sozzi, PhD, who is
working at the Kimmel Cancer Center on leave from the National Cancer Institute
of Milan, is the first author of the study.