Johns Hopkins Gazette: July 11, 1994

By Marjorie Centofanti

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 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 on 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," said team leader Andrew Feinberg, "but
until now, we had nothing to link 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 added. "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," Dr. Feinberg said. "It behaves like the
father's chromosome."
    With normal imprinting, he said, 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, Dr. Feinberg said.
    The imprinting is also switched in 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," Dr. Feinberg said. "We think that
having both a double dose of growth promoter and a lack of
this particular tumor suppressor gene encourages tumor
    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. Dr. Feinberg's team found the pattern of
methylation had switched on maternal chromosomes from Wilms'
    The study was funded by grants from the National
Institutes of Health.

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