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Andrew Feinberg, M.D.
Andrew Feinberg, M.D.


New Meaning to Genetics

Andrew Feinberg, M.D., considers himself a classically trained geneticist. Yet growing evidence he’s accumulated about a process called imprinting is challenging the view that humans carry two functioning copies of every gene, one from each parent. In imprinting, the copy inherited from one parent (sometimes the mother, sometimes the father) is active, while the same gene from the other parent is inactive.

“What we found is that it is normal to have only one functioning copy of imprinted genes, which is really a sea change in thinking,” says Feinberg. “Now we have to look at which parent the genes come from, and whether one or both is functioning.

Feinberg, a pioneer in the area of epigenetics—the science concerned with changes in genes other than the DNA sequence itself—says his interest in imprinting began while treating a patient with Beckwith-Wiedemann syndrome (BWS). Feinberg and his colleagues first mapped the gene responsible for this syndrome, which is characterized by prenatal overgrowth and childhood cancer, to chromosomal band 11p15. They then localized to a specific stretch of DNA a series of chromosomal rearrangements in this region, narrowing the gene hunt. Surprisingly, all of the chromosomal rearrangements turned out to be of maternal origin, suggesting that the two parental chromosomes were different, and that imprinting might play a role in the pathogenesis of the disease.

Based on this clue, Feinberg’s lab identified a group of imprinted genes, or “domain,” in this region—the first evidence of gene imprinting in humans.

What Feinberg coined “loss of imprinting” is another piece of the puzzle. In a study of Wilms’ tumors—malignancies in children’s kidneys—Feinberg’s lab had determined that 70 percent of the tumors had this loss of imprinting. This, they found, can activate the normally silent copy of imprinted growth-promoting genes and also silence the normally active copy of tumor suppressor genes. This appears to be one of the most common alterations in childhood and adult cancers.

Recent work in Feinberg’s lab suggests the loss of imprinting may help identify patients at risk for colon cancer.

—- GL