Newly Discovered Mutation Found in More Brain Tumors
A recent survey of genomic changes in brain tumors found that a gene called IDH1 was mutated in more than 10 percent of the glioblastoma tumors analyzed. The mutations tended to occur in younger patients and were associated with a somewhat longer survival compared with patients who lacked the mutations.
A follow-up study by researchers at the Duke University Medical Center and Johns Hopkins Kimmel Cancer Center now shows that IDH1 and a related gene, IDH2, are frequently altered in three types of gliomas, the most common form of brain cancer. These include low-grade astrocytomas, oligodendrogliomas, and secondary glioblastomas.
The mutations were not detected in nearly 500 other tumors from outside the central nervous system. And among gliomas, IDH mutations often occurred in lower-grade tumors, suggesting that the changes may help initiate and drive these cancers, the researchers reported in the February 19 New England Journal of Medicine (NEJM).
Until last year, IDH1, which is involved in producing energy for a cell, had not been associated with brain cancer. While it is not yet clear how the IDH mutations might affect the genes or cells, an analysis of 445 brain tumors showed that the mutations are localized to certain regions of the genes.
“These are very specific mutations,” said lead investigator Dr. Hai Yan of Duke University. The mutations may affect approximately 6,000 children and adults with brain cancer in the United States each year, the researchers estimate.
The study confirmed the earlier finding that patients whose glioblastomas carried IDH1 mutations had improved outcomes over those whose tumors did not, and it extended the finding to include IDH2 mutations. Patients with a glioblastoma carrying mutations in either gene survived on average 31 months, versus 15 months for those without the mutations.
In addition, patients with anaplastic astrocytomas that tested positive for the mutations had a median survival of 65 months, compared with 20 months for those who did not. (It was not possible to compare survival data for patients with oligodendrogliomas because there were not enough tumors that lacked the mutations.)
The researchers believe, based on these results and studies of the mutations in cultured cells, that gliomas with IDH mutations are a clinically and genetically distinct group of tumors. If this is confirmed, the mutations could be a marker for classifying patients with similar types of disease and prognoses, as well as provide leads for developing therapies targeted at the underlying changes in these tumors.
“As a next step, we need a better understanding of how the mutations might contribute to cancer,” said coauthor Dr. D. Williams Parsons, a visiting professor at Johns Hopkins and an assistant professor at Baylor College of Medicine.
“And from a clinical perspective,” he continued, “it will be important to follow patients with these mutations and see whether they have better or worse outcomes or responses to specific therapies.”
Because IDH genes encode metabolic enzymes, Dr. Yan noted, studying the mutations could lead to new insights into possible connections between metabolism and cancer. This is an area of growing interest among researchers and the subject of an accompanying editorial in NEJM by Dr. Craig Thompson of the University of Pennsylvania School of Medicine.“A potential benefit of identifying metabolic-enzyme mutations that are pathogenic in specific cancers is that such cancers may be susceptible to pharmacologic manipulations that are more effective and less toxic than existing therapies,” Dr. Thompson concluded.
—Edward R. Winstead