RESEARCHERS DISCOVER NOVEL GENE THAT MAY SUPPRESS COLON CANCER
15 May 2004 - Case Western Reserve University

The study, headed by Sanford D. Markowitz, and colleagues at CWRU's School of Medicine and University Hospitals of Cleveland, found that inactivating the helicase-like transcription factor gene has a role in transforming normal colon cells into cancer cells. They also found that reactivating the genetic protein appears to be related to suppressing colon cancers.

Involved in the study were the CWRU departments of Medicine and Epidemiology and Biostatistics, Ireland Cancer Center, UHC Research Institute and the Howard Hughes Medical Institute of Cleveland. Other institutions involved in the study were the University of Texas at MD Anderson Cancer Center in Houston, The Ohio State University, Columbia University and the University of Texas Southwestern Medical Center in Dallas.

"This is the first time a protein in this (gene) family has been implicated as a participant in a major, common form of cancer," Markowitz, a Howard Hughes Medical Institute investigator and member of the National Colorectal Cancer Research Alliance advisory board, said in a statement.

The study, "HLTF Gene Silencing in Human Colon Cancer," was reported in a recent issue of the Proceedings of the National Academy of Sciences.

"This is a new colon cancer suppressor gene whose inactivation appears to contribute to malignancy in about 40 percent of cases. Understanding what this gene does in the cell will help us comprehend how colon cancer gets started and could be a new target for drug intervention," Markowitz added.

Colon cancer is the second leading cause of cancer death in adult Americans.

Scientists examined colon cancer cells and normal cells from 63 colon cancer patients and 34 colon cancer cell lines grown in a laboratory. They found that HLTF protein production had been shut down by DNA methylation, which produces an abnormal "off switch" that shuts down production of a tumor suppressor protein. When scientists introduced a functional copy of the HLTF gene into the colon cancer cell lines that lacked the gene, the cancer cells stopped growing.

Scientists also found that those tumors with the silenced HLTF gene were actually less likely to spread. That may suggest that tumors with HLTF turned off may grow more slowly than other tumors.

Markowitz and his colleagues also looked at lung and breast cancer cells, but found the HLTF gene to be normal, suggesting that the HLTF gene may be specific to colon cancer.

This finding suggests that the HLTF gene itself is a tumor suppressor gene that can stop tumors from growing. In the short term, Markowitz said the findings might help doctors diagnose colon cancer and possibly tell the difference between aggressive, invasive tumors and less aggressive forms of colon cancer. The study also may lead to new drug treatments, now in the early developmental stages, that reverse methylation.

Markowitz said the methylated HLTF gene could be a target for a new diagnostic test for colon cancer because scientists had previously found abnormal methylated DNA in the blood of some colon cancer patients. This follows a recent discovery by Johns Hopkins University School of Medicine researcher Bert Vogelstein, who found a new, non-invasive, DNA-based test for colon cancer using the APC tumor suppressor gene.

"What we describe in this paper is a test that can catch 40 percent of colon cancers," Markowitz said. "A screen that searches for APC and HLTF mutations may be able to catch more than 90 percent of cancers, making blood or stool sampling practical."

People whose colon cancer is detected in the early stages, when recovery is better. Colonoscopy, the current standard for detection, is invasive and avoided by people who may benefit from the test.

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