Scientists at the Johns
Hopkins Kimmel Cancer Center and Duke University
Medical Center have linked mutations in two genes, IDH1 and
IDH2, to nearly three-quarters of several of the most
common types of brain cancers known as gliomas. Among the
findings: People with certain tumors that carry these
genetic alterations appear to survive at least twice as
long as those without them. Further research on the genes
could lead to more precise diagnosis and treatments, they
said.
Reporting in the Feb. 19 issue of the New England Journal
of Medicine, scientists say they looked for IDH1 and IDH2
gene alterations in material taken from 500 brain tumors
and 500 non- central nervous system cancers. They located
changes in the IDH1 gene in more than 70 percent of three
common types of gliomas: low-grade astrocytomas,
oligodendrogliomas and secondary glioblastomas. The changes
occurred within a single spot along a string of thousands
of genetic coding letters. Some of the brain cancers that
did not have alterations in IDH1 had equivalent mutations
in another closely related gene, IDH2.
"For patients with these types of common brain tumors,
mutations of IDH1/IDH2 are the most frequent genetic
alterations yet identified," said D. Williams Parsons,
visiting professor in
pediatric oncology at Johns Hopkins and assistant
professor at Baylor College of Medicine.
Further analysis of their data showed that glioblastoma
and anaplastic astrocytoma patients carrying the mutations
survived longer than those who did not, and note that
additional studies of how the gene works may reveal why
this occurs. The median survival for glioblastoma patients
with mutations in either IDH1 or IDH2 was 31 months versus
15 months for those lacking the mutations. Anaplastic
astrocytoma patients carrying the mutations were found to
have a median survival of 65 months as compared with 20
months for those who did not. The scientists say that they
could not compare survival data in oligodendroglioma
patients because there were too few tumors that did not
carry the mutations.
"Gliomas with IDH1/IDH2 mutations clearly make up a
clinically and biologically distinct subgroup of brain
cancers that may benefit from targeted therapies in the
future," Parsons said.
IDH1, which stands for isocitrate dehydrogenase 1, was
first spotted last year in results from a genomewide scan
of brain cancer mutations led by the Johns Hopkins
scientists. At the time, the scientists linked mutations in
the IDH1 gene to roughly 12 percent of glioblastomas (or
glioblastoma multiforme), the most lethal form of
glioma.
Add to this the newly discovered mutations occurring in
lower grade astrocytomas and oligodendrogliomas, and
Parsons estimates that 6,000 adults and children with brain
cancer per year in the United States could be affected.
"Pathologists may find it useful to determine IDH1/IDH2
status to help identify and classify these cancers,"
Parsons said. He added that proper diagnosis is essential
because treatments differ within types of gliomas, as well
as other forms of brain cancer.
Victor Velculescu, associate professor and director of
cancer genetics at the Ludwig Center at Johns Hopkins,
said, "New treatments could be designed to target the
enzymatic activity that is altered by these mutations."
"The mutations appear to occur very early in the
progression of these cancers, perhaps at the stem cell
level," added Bert Vogelstein, Clayton Professor and
co-director of the Ludwig Center and a Howard Hughes
Medical Institute investigator.
Mutations were found by a standard technique of amplifying
sections of the IDH1 and IDH2 genes through polymerase
chain reaction, a process that replicates bits of DNA to
levels that can be detected by sensitive computer
equipment.
The research was funded by the Pediatric Brain Tumor
Foundation Institute, Damon Runyon Foundation, Southeastern
Brain Tumor Foundation, Alex's Lemonade Stand Foundation, V
Foundation for Cancer Research, Virginia and D.K. Ludwig
Fund for Cancer Research, Pew Charitable Trusts, American
Brain Tumor Association, Brain Tumor Research Fund at Johns
Hopkins, Beckman Coulter and Accelerate Brain Cancer Cure
Foundation.
Collaborating scientists include Hai Yan, Genglin Jin,
Roger McLendon, B. Ahmed Rasheed, Ivan Kos, Ines
Batinic-Haberle, Henry Friedman, Allan Friedman, David
Reardon, James Herndon and Darell D. Bigner, all of Duke
University Medical Center; Sian Jones, Gregory Riggins and
Kenneth Kinzler, all Johns Hopkins; and Weishi Yuan, of the
Food and Drug Administration.
Yan, Parsons, Jones, Kinzler, Velculescu, Vogelstein and
Bigner are eligible for royalties received by Johns Hopkins
University on sales of products related to research
described in this article, under licensing agreements
between the university and Beckman Coulter. These
agreements are being managed in accordance with policies at
The Johns Hopkins University.
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