原文
Two Gene Mutations Linked To Most Common Brain Cancers And Longer
Survival
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 also 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," says D. Williams Parsons, M.D.,
Ph.D., 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," says Parsons.
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
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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 U.S. could be affected.
"Pathologists may find it useful to determine IDH1/IDH2 status to help identify and
classify these cancers," says Parsons. He added that proper diagnosis is essential
because treatments differ within types of gliomas, as well as other forms of brain
cancer.
"New treatments could be designed to target the enzymatic activity that is altered by
these mutations," says Victor Velculescu, M.D., Ph.D., associate professor and
director of cancer genetics at the Ludwig Center at Johns Hopkins.
"The mutations appear to occur very early in the progression of these cancers, perhaps
at the stem cell level," adds Bert Vogelstein, M.D., Clayton Professor and co-director
of the Ludwig Center at Johns Hopkins 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 (PCR), 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, the
Damon Runyon Foundation, the Southeastern Brain Tumor Foundation, Alex's
Lemonade Stand Foundation, the V Foundation for Cancer Research, the Virginia and
D.K. Ludwig Fund for Cancer Research, the Pew Charitable Trusts, the American
Brain Tumor Association, the Brain Tumor Research Fund at Johns Hopkins,
Beckman Coulter, and the Accelerate Brain Cancer Cure Foundation.
Collaborating scientists include Hai Yan, M.D., Ph.D., Genglin Jin, Ph.D., Roger
McLendon, M.D., B. Ahmed Rasheed, Ph.D., Ivan Kos, Ph.D., Ines Batinic-Haberle,
Ph.D., Henry Friedman, M.D., Allan Friedman, M.D., David Reardon, M.D., James
Herndon, Ph.D., and Darell D. Bigner, M.D., Ph.D., at Duke University Medical
Center; Sian Jones, Ph.D., Gregory Riggins, M.D., Ph.D., and Kenneth Kinzler, Ph.D.,
from Johns Hopkins; and Weishi Yuan, Ph.D., from 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
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文摘
N Engl J Med. 2009 Feb 19;360(8):765-73.
IDH1 and IDH2 mutations in gliomas.
Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I,
Batinic-Haberle I, Jones S, Riggins GJ, Friedman H, Friedman A, Reardon D,
Herndon J, Kinzler KW, Velculescu VE, Vogelstein B, Bigner DD
Department of Pathology, Pediatric Brain Tumor Foundation Institute, Duke
University Medical Center, Durham, NC 27710, USA. yan00002@mc.duke.edu
BACKGROUND: A recent genomewide mutational analysis of glioblastomas (World
Health Organization [WHO] grade IV glioma) revealed somatic mutations of the
isocitrate dehydrogenase 1 gene (IDH1) in a fraction of such tumors, most frequently
in tumors that were known to have evolved from lower-grade gliomas (secondary
glioblastomas). METHODS: We determined the sequence of the IDH1 gene and the
related IDH2 gene in 445 central nervous system (CNS) tumors and 494 non-CNS
tumors. The enzymatic activity of the proteins that were produced from normal and
mutant IDH1 and IDH2 genes was determined in cultured glioma cells that were
transfected with these genes. RESULTS: We identified mutations that affected amino
acid 132 of IDH1 in more than 70% of WHO grade II and III astrocytomas and
oligodendrogliomas and in glioblastomas that developed from these lower-grade
lesions. Tumors without mutations in IDH1 often had mutations affecting the
analogous amino acid (R172) of the IDH2 gene. Tumors with IDH1 or IDH2
mutations had distinctive genetic and clinical characteristics, and patients with such
tumors had a better outcome than those with wild-type IDH genes. Each of four tested
IDH1 and IDH2 mutations reduced the enzymatic activity of the encoded protein.
CONCLUSIONS: Mutations of NADP(+)-dependent isocitrate dehydrogenases
encoded by IDH1 and IDH2 occur in a majority of several types of malignant gliomas.
2009 Massachusetts Medical Society
PMID: 19228619 [PubMed - indexed for MEDLINE]
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