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By discovery of a novel gene, medical researchers
have taken a step toward better understanding and perhaps earlier
detection and improved chance of cure of 40 percent of human colon
cancers.
The study, headed by Sanford D. Markowitz,
and colleagues at CWRU's School of Medicine and University Hospitals
of Cleveland (UHC), found that inactivating the helicase-like
transcription factor (HLTF) 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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