BioWorld International Correspondent

LONDON - The discovery of a gene that is absent from most samples of lung tumors could one day lead to a screening test to detect the disease before it has spread, or even to new drugs to treat it.

The gene, LIMD1, normally is found on chromosome 3p21 in a region that often is missing from solid tumors, including those of the colon, ovary, stomach and kidneys.

Chris Boshoff, professor of cancer medicine at University College London, told BioWorld International: "If we can establish that loss of this gene is an early event in the development of cancer and occurs before the person develops invasive cancer, then it may be possible to develop a sputum test to screen people - particularly smokers - who are at high risk of developing lung cancer. We hope that this finding could also lead to new drugs to treat lung cancer, but we recognize that replacing the missing protein would be difficult to achieve, given that gene therapy would have to be involved."

The work is reported in the Nov. 8, 2004, issue of the Proceedings of the National Academy of Sciences, in a paper titled "LIM domains-containing protein 1 (LIMD1), a tumor suppressor encoded at chromosome 3p21.3, binds retinoblastoma protein (pRB) and represses E2F-driven transcription."

As part of their work studying how viruses cause cancer, Boshoff and his colleagues were attempting to investigate the role of viral proteins in the development of lymphoma. They were using a method called a yeast two-hybrid screen to identify proteins that interact with a known tumor-suppressor gene, the retinoblastoma protein.

Boshoff said: "Instead of identifying viral proteins, the screen pulled out this protein called LIMD1, and then we noticed that it was encoded on this region of chromosome 3p21, which is commonly deleted in tumors. This made us even more interested, because this region is known to be deleted in various cancers, which suggests that it contains various tumor-suppressor genes. What is more, we had already shown that LIMD1 interacts with the retinoblastoma protein, which is also a tumor-suppressor gene."

Further experiments by Tyson Sharp, a postdoctoral scientist on the team and first author of the paper, confirmed that the identified gene encoded the LIMD1 protein, and that it interacts with the retinoblastoma protein. Sharp also showed that the gene is absent from many cancer cell lines, and that when it is added to cancer cell lines, their growth is inhibited.

The team used a mouse model of lung cancer for additional studies. In the model, lung cancer cell lines are injected into the tail vein of the animals. Normally, they migrate to the lungs and form lung metastases.

But when Boshoff and his colleagues restored the function of LIMD1 in those cells before injecting them, they no longer went on to form lung metastases.

Finally, the group tested lung tumors from 14 patients for the presence or absence of LIMD1 and compared the results with tests on adjacent normal lung tissue. They found that all of the tumor samples had significantly decreased levels of messenger RNA for LIMD1, compared with the adjacent normal lung tissue. "This fits with the hypothesis that LIMD1 is a tumor-suppressor gene," Boshoff said.

Plans for the future include finding out exactly how LIMD1 interferes with cell growth.

"We also want to discover if this gene is deleted in other types of epithelial malignancies like breast and ovary," Boshoff said. "We need to find out if loss of LIMD1 function is due to mutations in the gene itself, or the result of abnormal gene expression. It will also be important to discover if its loss is an early event in cancer development or a late event. If it is early, it may be possible to use this information to develop a screening test to identify those at highest risk of lung cancer."

Other studies will look at whether constituents of tobacco smoke could be partly responsible for damaging the gene.