Study May Explain Gene's
Link to Childhood Cancer
Excerpt By Amy Norton, Reuters Health

NEW YORK (Reuters Health) - Scientists may have found out why a specific mutation in the tumor-suppressing p53 gene is linked solely to childhood cases of a cancer of the adrenal gland.

Previous research has linked the p53 mutation to the heightened incidence of adrenocortical cancer among Brazilian children. In fact, one study showed that 35 of 36 children in southern Brazil who developed adrenal gland tumors harbored the mutation.

Adrenocortical cancer, which affects the outer layer of the hormone-producing adrenal gland, is a relatively rare disease. Still, compared with the worldwide rate, children in Brazil have anywhere from 100 to 500 times the risk, according to Dr. Richard W. Kriwacki, who led the new study. He said researchers believe the cancer involves both environmental and genetic factors.

The p53 gene acts as a tumor suppressor and is commonly mutated in a range of cancers. But one p53 mutation known as R337H has been linked only to pediatric adrenocortical cancer.

Now Kriwacki and his Tennessee colleagues may have discovered why. The mutation appears to be dependent on the acid-alkaline balance--or pH level--in cells, according to their report in the advance online edition of Nature Structural Biology for January. When the mutation is in a less-acidic environment--as might occur in adrenal cells during development--it appears to ``destabilize'' the p53 gene, hindering its tumor-fighting ability.

The ultimate goal of studying such molecular details is to figure out a way to prevent cancer from developing in children who carry the gene mutation, Kriwacki, of St. Jude's Children's Research Hospital in Memphis, told Reuters Health.

He noted that affected children typically develop the cancer between the ages of 2 and 6, and the death rate is roughly 50%.

Kriwacki and his colleagues came to their conclusions after studying the structure and stability of a particular domain in the p53 gene. They compared normal p53 with the R337H-mutated form.

The researchers found that in a higher-pH, or less-acidic, environment, the mutation created instability in the p53 region they studied.

According to Kriwacki, elevated pH within adrenal cells may explain the mutation's exclusive link to childhood adrenocortical cancer.

The adrenal gland, he explained, goes through ``extensive cellular remodeling'' during the prenatal and newborn period. Along the way, some cells go through apoptosis, or ``cell suicide.'' Such cells have been found to have elevated pH levels.

SOURCE: Nature Structural Biology advance online 2001;10.1038/nsb730.

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