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Gene loss creates age- and gender-dependent cancer syndrome in mice

Researchers at the Johns Hopkins Kimmel Cancer Center have discovered that loss of a gene already implicated in human cancers also leads to age- and gender-linked cancers in mice. The findings, reported in the February issue of Nature Genetics, validate the gene's dysfunction as an early step in development of cancer in people, the scientists say.

Screening tumor samples for genes with too many methyl groups attached, a few years ago a Johns Hopkins graduate student, Michele Makos-Wales, found hypermethylated-in-cancer 1 (Hic1). Methyl groups are one of many types of additions to the DNA sequence that help control gene expression.

"Most genes linked to cancer were first identified from mutations in families, and subsequently some of the same genes were found to be hypermethylated, but Hic1 was identified solely because of extra methylation in cancer cells," says Stephen Baylin, Ph.D., professor in the cancer biology division. "Now we've shown directly that loss of the gene's function leads to cancers in mice."

The finding also provides a powerful message to other scientists studying genes linked to cancer through "epigenetic" changes like abnormal methylation. While genes whose cancer-causing abilities are traced to mutations in the DNA sequence have long been studied in "knockout" mice, this is the first evidence that knockout mice can also reveal the cancerous effects of epigenetic problems, Baylin says.

Since excess methylation turns the gene off, former graduate student Mark Carter and the team tried to measure its impact on cancer by completely knocking out Hic1 in mice, but the mice died before birth. So they switched to studies of mice with only one copy of the gene.

"For a long time, nothing happened," says postdoctoral fellow WenYong Chen, Ph.D., who led the research team. In fact, not until the mice were more than 70 weeks old -- "pretty old for a mouse," he says -- did excessive cancers begin to appear. By 90
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Contact: Vanessa Wasta
wastava@jhmi.edu
410-955-1287
Johns Hopkins Medical Institutions
7-Feb-2003


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