STUDY SHOWS IMPRINTING DIRECTLY TIED TO CANCER

June 24, 1994
Media Contact:Joann Rodgers
Phone: (410) 955-8659
E-mail: JRodgers@welchlink.welch.jhu.edu

A chromosome from your mother that "thinks" it came from your father may be necessary to initiate some forms of cancer, according to studies at Johns Hopkins and the University of Michigan, reported in the July 1 issue of Nature Genetics.

The work, with an earlier study in Nature by the same research team, is the first evidence that links an unusual genetic process called imprinting with human cancer, in this case a childhood kidney cancer called Wilms' tumor.

Imprinting is a normal process in which chromosomes, and thus some of the genes they carry, are "marked" differently and behave differently depending upon whether they came from a person's mother or father -- even if the genes are identical.

"We've long suspected that imprinting is an important process in cancer," says team leader Andrew Feinberg, M.D., "but until now, we had nothing to it directly with the disease in humans.

"A lot of new evidence says imprinting may be a key step in cancer, both in Wilms' tumor and in other more common malignancies such as lung cancer," he adds. "And unlike mutations, errors of imprinting are something which are conceivably easier to fix."

The team focused on two imprinted genes, neighbors on human chromosome 11. One gene, called IGF2 (for insulinlike growth factor II), is a growth-promoter active in many tumors. The other, called H19, is a suspected tumor suppressor gene.

Comparing cells from kidneys of normal children with cells from Wilms' tumor patients, the researchers found a high proportion of the tumors with evidence of abnormal imprinting. This probably led to double doses of cancer-promoting chemicals and an absence of normal tumor suppressing action.

"In the case of Wilms' tumor, the imprinting -- the sexual identity -- of the chromosome 11 the child inherits from the mother is switched, 11 says Feinberg. "It behaves like the father's chromosome."

With normal imprinting, he says, the mother's IGF2 gene is inactive. Yet in the tumor tissue, that gene is apparently turned on. The tumors have almost twice the amount of IGF2 as do normal cells, says Feinberg.

The same is true for the H19 gene. The normally active gene from the mother has been turned off. "Since the father's gene is already off because of imprinting, these children are left, apparently, with no H19 tumor suppression at all.

"We think that having both a double-dose of growth promoter and a lack of this particular tumor suppressor gene encourages tumor growth," says Feinberg.

Further proof that this switch occurs in the chromosome from the mother comes from the researchers' studies of DNA in normal and tumor cells. Scientists have noted certain physical changes (called methylation) in DNA that's imprinted. Feinberg's team found the pattern of methylation had switched on the matemal chromosomes from the Wilms' tumors.

Co-researchers in the study are Marja Steenman, Shirley Rainier and Craig Dobry in Feinberg's lab; Paul Grundy of the Cross Cancer Institute, Edmonton, Alberta; and Isabelle Horon with the Maryland Center for Health Statistics, Baltimore.

The study was funded by NIH grants.


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