© 1999 by Oxford University Press
Journal of the National Cancer Institute, Vol. 91, No. 1, 16-18,
January 6, 1999
© 1999 Oxford University Press
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Gene Imprinting: Making an Impression on Cancer Research
Restoring a normal process known as genomic imprinting may furnish researchers with a novel way of preventing and treating many cancers in the future. Imprinting involves an exquisitely small number of genes where one copy inherited from one parent is active, while the same gene from the other parent is inactive or silent. When cancer occurs, this balance is somehow perturbed.
Gene imprinting really is "gene expression dependent on parental origin," said Wolf Reik, M.D., head of the Developmental Genetics Program at Babraham Institute in England. "Some genes in the genome — a minority of genes on the order of less than 0.1% — are expressed or repressed depending exclusively on where they come from, whether it is the mother or father."
Altogether, some 30 genes in the genome are known to be imprinted, although researchers believe there are probably many more yet to be identified. In a handful of cases, both copies of the maternally or paternally derived genes become active, resulting in a loss of imprinting (LOI). This loss may be a key step in the onset and progression of cancer.
Explained Reik, because a previously silent allele is now expressed, there is an increase or generally altered gene dosage at specific areas or loci, depending on the gene in question. This is relevant, he said, because a "very important category of imprinted genes are involved in fetal growth and cell proliferation" — implying that LOI affects areas known to be associated with cancer.
LOI alterations or disruptions appear to occur commonly in both childhood and adult malignancies, leading to altered expression of growth regulatory genes, and "potentially reversible changes," said Andrew Feinberg, M.D., professor of medicine at Johns Hopkins University School of Medicine, Baltimore.
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Recent findings show that a loss of genomic imprinting might be reversed by DNA methylation inhibitors — drugs that alter DNA structurally — such as 5-aza-2'-deoxycytidine. Studies have shown that when these drugs were used, normal imprinting was restored. These drugs may prove useful in the treatment of tumors shown to have LOI, either alone or in conjunction with other agents, asserted Feinberg.
Another finding by Feinberg and his colleagues showed that 91% of colorectal cancer patients whose tumors had a DNA defect known as microsatellite instability also had a loss of imprinting.
According to Feinberg, this suggests that LOI in tumor and in normal tissue may help
identify those colorectal patients either with cancer or at risk of developing cancer. In addition,
44% of the patients had LOI of a specific gene — insulin-like growth factor 2 —
which has been implicated in a variety of cancers including lung, colon, breast, and
Wilms' tumor (see News, Sept. 3, 1997).
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"There may be a potential link between DNA replication and genomic imprinting," said Feinberg. "In the future this understanding may lead to a useful predictive test for cancer."
Meanwhile, Reik, who is researching the mechanisms of control of imprinting, said that the major mechanism is DNA methylation whereby imprinted genes get differentially methylated — or altered structurally — in the parental gametes, in eggs and sperm, and "that is inherited."
But he also described two other ways in which imprinting may be lost; one is mutations in specific areas of the imprinted genes, and the other is by nonmutational mechanisms — termed epigenetic — due to environmental instances which are ill-defined.
"Since LOI is observed in many cancers, understanding the mechanism can prevent it [LOI] from happening or allow therapeutic intervention to correct it when cancer is already present," Reik said.
Although the ability to control or manipulate methylation patterns is not yet available, some researchers feel such knowledge is imminent. "I think there are answers very close by that will give us a chance to manipulate the patterns and turn things on and off based on methylation," projected Konrad Huppi, Ph.D., a National Cancer Institute researcher in this area.
Cancer Links
"There is no doubt imprinting plays a role in cancer," said Dan Driscoll, M.D., associate professor of pediatrics and molecular genetics at the University of Florida College of Medicine. Driscoll foresees a promising role in early diagnosis in which one may be able to define certain risk factors for a particular cancer, such as family history, and apply a simple test to check the status of a known imprinted gene — such as IGF2. LOI would alert clinicians to keep a close eye and perhaps utilize colonoscopies more often in the case of colon cancer and mammographies in the case of breast cancer, for example. "Early detection leads to early treatment," commented Driscoll.
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Scope of Work
According to Reik, there has been an explosion of work in the area of imprinting due to its human disease relevance. "I think imprinting is going to be involved in a number of birth defects, genetic diseases, and cancer," agreed Driscoll. "The processes are similar although the disease manifestations may be very different.
"It is an incredibly complicated, difficult, and evolving story but there is certainly a smoking gun here surrounding imprinting and DNA methylation patterns," he said. "If we understand what is broken and how something is broken, maybe there will be a way to restore the imprint in a selective manner."
Added Feinberg, "It is difficult to conceive of strategies in which one would replace a missing or defective copy of a gene, such as a tumor suppressor gene. On the other hand, if you have something like imprinting, at least it is easier theoretically and, in fact practically now in the lab, to develop a strategy that might restore normal imprinting. It might actually be a new arrow in our quiver of cancer treatments."
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