Scientists Find Unusual Lung-cancer Tumor-suppressor Gene

The gene, known as TCF21, is silenced in tumor cells through a chemical change known as DNA methylation, a process that is potentially reversible.

The findings might therefore lead to new strategies for the treatment and early detection of lung cancer, a disease that killed an estimated 163,510 Americans in 2005. The study could also lead to a better understanding of the molecular changes that occur in tumor cells during lung-cancer progression.

Tumor-suppressor genes are genes that normally prevent cells from growing out of control. The loss or silencing of one or more tumor-suppressor genes is believed to be an important part of cancer development.

The study, by researchers at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, was published online in the Jan. 13 early edition of the Proceedings of the National Academy of Sciences.

The newly discovered gene is unusual because it can alter normal epithelial cells, causing them to change to a more primitive state. Epithelial cells form the skin and line the body's passageways and hollow organs. They are also the source of the most common forms of cancer.

The more primitive cell type, known as a mesenchymal cell, is more commonly found in embryos and is capable of migrating to other tissues. This suggests that the silencing of the TCF21 gene might help a tumor to spread to other areas of the body, a process known as metastasis.

The gene is also often silenced or lost in a variety of other cancers, including breast and ovarian cancer, melanoma and lymphoma.

“The fact that this gene is silenced in many cancer types strongly suggests that it plays an important role in cancer development,” says principal investigator Christoph Plass, a professor of molecular virology, immunology and medical genetics and a researcher in the OSU Human Cancer Genetics Program.

In addition, says first author Laura T. Smith, a postdoctoral fellow in Plass' laboratory, “because this gene is silenced by DNA methylation, it might be possible to reactivate it using drugs that reverse the methylation process. This could provide a new strategy for treating these cancers.”

The gene is found on chromosome 6 in a region known as 6q23-24, an area that contains hundreds of genes. Other researchers have searched this region looking for mutations that might lead them to a silenced tumor-suppressor gene, but, Plass says, “that strategy has been unsuccessful.”

DNA methylation, which is a chemical change and not a mutation, is another way that genes are silenced. For this study, Plass and his colleagues systematically scanned the same chromosome region using a technology known as restriction landmark genome scanning, which identifies methylated genes.

The researchers examined the region in about 50 tumor samples from patients with head and neck squamous-cell carcinomas and with non-small-cell lung cancer, which is responsible for about 85 percent of lung cancer cases. From this, they identified TCF21 as a gene often silenced by methylation compared with normal airway cells.

“A picture is emerging that certain genes tend to be silenced mainly by DNA methylation, while others tend to be silenced by genetic mutations,” Plass says. “This gene seems to be silenced by DNA methylation.”

Through a series of experiments, Plass and his colleagues showed that an active TCF21 gene can, in fact, be silenced by DNA methylation, and that drugs that reverse methylation can reactive it.

The researchers also used a lung-cancer cell line to show that if the active version of the TCF21 gene is placed in tumor cells, the active gene will slow the cells' growth rate.

Lastly, the researchers showed that mice injected with lung-tumor cells that had an active TCF21 gene developed tumors that were two to three times smaller than tumors that developed from cancer cells with a silent TCF21 gene.

Plass and his colleagues are now studying the possible role of TCF21 in metastasis.

Funding from the National Cancer Institute and the National Institute of Dental and Craniofacial Research supported this research.