Mar. 27, 2001 By focusing on molecular differences that define distinct types of childhood leukemia, scientists have discovered that vulnerability to one type of the cancer or another depends on something as simple as which form of a single enzyme a child inherits.
The discovery, led by a molecular epidemiologist at the University of California, San Francisco, highlights the impact even minor genetic variation can have on disease, and also shows how distinguishing subtle disease differences can help reveal causes that would otherwise be masked, the scientists say.
The research indicates that children are protected against different types of leukemia depending on which form of an enzyme they have for metabolizing folic acid.
The research is being presented March 26 at the annual meeting of the American Association for Cancer Research, and is being published March 27 in the Proceedings of the National Academy of Sciences.
"Currently we understand almost nothing about the causes of childhood leukemia, but such an understanding is essential if we hope to prevent this tragic disease," said Joseph Wiemels, PhD, lead author on the paper and assistant professor of epidemiology and biostatistics at UCSF."Our research suggests that scrutiny of genetic changes in leukemia cells -- at the DNA level -- can reveal potential causes specific to each type of leukemia."
Wiemels collaborated on the research with colleagues in England and Scotland.
The United States is among the countries with the highest rates of childhood leukemia in the world, Wiemels said, with about 3,500 children in the U.S. developing the cancer each year. Cancer biologists now recognize at least three subtypes of childhood leukemia, based on different abnormalities in the chromosomes. Each subtype has a different prognosis and treatment protocol, but causes remain unknown and treatments often create other serious medical problems.
Until now, there has been no indication that these three leukemia subtypes develop in different ways. In one type, known as hyperdiploid, children have extra copies of chromosome 21 as well as other chromosomes. Two other forms are known as translocation subtypes, characterized by abnormal chromosomes formed during development of the blood cells before the child is born.
In the new study, the scientists used molecular probes to classify 253 British childhood leukemia patients into one of three leukemia disease categories. They then examined the children's DNA using gene-sequencing techniques to determine which of three common forms of a certain enzyme each child had. The enzyme, known as MTHFR, is one of two dozen in the body involved in metabolizing the vitamin folic acid, found in fresh fruits and vegetables and critical to prevent abnormal nerve development in the fetus and colon cancer and heart disease in adults. The consensus on the vitamin's benefits led the FDA in 1997 to require folic acid enrichment in flour and corn products in the United States.
Folic acid is shunted through several biochemical pathways in the body, and scientists already knew that inadequate amounts of the vitamin - due to low dietary supply or poor performance by enzymes that metabolize it - leads to defects in the way DNA is replicated in the cells.
In the PNAS paper, the researchers report finding that children with a "low-functioning variant" of MTHFR - one that is relatively poor at metabolizing folic acid - appear to be protected against one of the translocation-type leukemias, known as MLL. A different low-functioning variant appeared to be protective against hyperdiploid leukemia, they reported.
"We know that inadequate folic acid in the body leads to improper DNA replication, and that this may increase cancer risk," Wiemels said. "Earlier studies have shown that low-functioning alleles of MTHFR prompt the body to set aside more folic acid for DNA synthesis -probably a trait evolved as insurance against major DNA damage in times of folic acid undernourishment, which is common during pregnancy.
"Now we have shown that the low-functioning allele protects against the MLL leukemia subtype. It is likely that by assuring adequate folic acid for DNA processing, the enzyme variant is helping to prevent DNA breakage that would lead to MLL translocations."
The situation is somewhat different for hyperdiploid leukemia: In this case a second low-functioning variant of MTHFR protects against this leukemia subtype, probably by altering a second biochemical pathway by which folic acid affects DNA or chromosome structure, Wiemels said.
MTHFR is just one of two dozen enzymes involved in folic acid metabolism, which means, Wiemels pointed out, that there are probably many dozen enzyme variants which may be providing different levels of protection or vulnerability to different types of leukemia.
"Although the causes of childhood leukemia are essentially unknown, we have implicated folic acid in this serious disease for the first time," Wiemels said. And while the U.S. now assures adequate folic acid in the diet by supplementing flour and corn products, he said, the new findings may help explain the historically high level of childhood leukemia in California in general and among Hispanic populations in particular.
Hispanic Americans, he notes, have historically had the highest U.S. rates of newborns with neural tube defects and similarly higher-than-normal rates of childhood leukemia. While use of folic acid supplements before and during pregnancy is increasing among this high-risk group, its use still lags somewhat, he said, and should be increased to avert childhood diseases.
Wiemels expects that the research will lead to more scrutiny of the role of folic acid and folic acid metabolism in causing childhood leukemia.
"Future studies may suggest methods to exploit folic acid biochemical pathways to treat leukemia," he suggested.
Colleagues in the research and co-authors on the paper with Wiemels are Mel .F. Greaves, PhD, professor of cell biology, and Rosalyn N. Smith, BS , both at the Institute of Cancer Research in London; G. Malcolm Taylor, PhD, professor of immunogenetics, Osborn B. Eden, MD, professor of haematology, both in hospitals in Manchester, England; and Freda E. Alexander, PhD, professor of epidemiology, at University of Edinburgh, Scotland.
The research was funded by the Kay Kendall Leukemia Fund and the Leukemia Research Fund, both of the United Kingdom.
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