ACTIVITY OF UNUSUAL GENES DISTINGUISHES DANGEROUS LEUKEMIA
COLUMBUS , Ohio – New research indicates that doctors can determine whether a person with chronic lymphocytic leukemia (CLL) has the most dangerous form of the disease or, instead, a more slowly progressing form.
They can do this by analyzing the activity of a newly discovered and unusual class of genes.
The study, led by researchers with The Ohio State University Comprehensive Cancer Center, is published in the Oct. 27 issue of the New England Journal of Medicine.
The research focused on genes for small molecules known as microRNAs (miRNAs). It showed that evaluating the pattern of expression, or gene signature, for 13 different miRNA genes reveals whether a patient has the fast or slow form of the disease.
“It's vital for oncologists to know which kind patients have so they can properly treat the disease,” says principal investigator Carlo M. Croce, professor and chair of molecular virology, immunology and medical genetics and director of OSU's Human Cancer Genetics Program.
“The slow form might not require treatment for many years, but the rapid form must be treated immediately and aggressively.”
The study by Croce and a group of colleagues also provides the first report of mutations in miRNA genes, including those that are inherited. “This strongly suggests that this new class of genes plays a role in development of the disease,” Croce says.
Inherited mutations, also known as germline mutations, are present at birth and can make a person more susceptible to cancer later in life. Thus, the germline mutations discovered by Croce and his colleagues may be cancer susceptibility genes for CLL.
“If this proves to be the case, testing for these mutations could identify people who are at an increased risk for CLL,” Croce says. In addition, the pattern shown by the mutations, he says, “strongly suggests that two of the miRNA genes are tumor-suppressor genes.”
The study led by Croce evaluated the activity of miRNA genes in CLL cells from 94 patients.
Using DNA microarray technology, the researchers examined 190 different miRNA genes in each sample to determine if the genes were active or inactive in CLL cells compared with normal cells (CLL is a cancer of B lymphocytes).
DNA microarray technology allows researchers to analyze thousands of genes at one time to determine whether they are switched on or off. Croce and his colleagues developed the gene microarray that was used to test the 190 miRNA genes for activity.
Of the miRNA genes analyzed, the researchers found that the activity pattern of 13 of them accurately predicted whether a person had the slow- or fast-progressing form of CLL.
In addition, the researchers sequenced 42 miRNA genes that they had isolated from 40 cases of CLL and from three healthy individuals. When the investigators identified an abnormal sequence in one of the 40 CLL cases, they then screened for the abnormality in DNA from 35 additional CLL cases (for a total of 75 CLL cases) and from 160 healthy individuals.
In all, the investigators found mutations in 12 percent (five of 42) of the miRNA genes examined, and one or more of these mutations were present in 15 percent (11 of 75) of the CLL cases. None of the mutations were found in the 160 healthy cases.
CLL is the most common form of leukemia worldwide, with more than 9,700 new cases diagnosed annually in the United States. There is no cure.Other OSU researchers involved in this study were George Adrian Calin, adjunct assistant professor of molecular virology, immunology and medical genetics; and Massimo Negrini, assistant professor of molecular virology, immunology and medical genetics.
Funding from the National Cancer Institute, the Italian Ministry of Public Health, the Italian Ministry of University Research, the Italian Association for Cancer Research and a Kimmel Scholar Award supported this research.
#Contact: Darrell E. Ward, Medical Center Communications, 614-293-3737, or Darrell.Ward@osumc.edu