Jefferson Study Points to Altered FHIT Gene As Important Cause of Different Lung Cancers

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 genetic instability.

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.