Elusive gene mutations found for malignant brain tumor

A discovery by scientists at Duke University Medical Center and the Johns Hopkins University could increase the chances of an effective combination of drug therapy for the treatment of the second most common type of brain tumor.

For years scientists have been looking for the primary cancer genes that are involved in the development of oligodendrogliomas. Scientists knew the two chromosomes that the likely mutations, but not the particular gene information held.

Now scientists have of Duke and Johns Hopkins discovers the most probable genetic mutations that researchers have for his yacht on chromosomes 1 and 19. These genes were hard to find until the technology improved, said Hai Yan, M.D., Ph.d., Duke Associate Professor of pathology and co-corresponding author of the study.

"The team used whole genome sequencing technology so no genes would be excluded, and to our surprise we found that one gene on chromosome 19, was mutated in six of the seven original tumor specimens that we sequenced," said Yan. "A mutation rate of 85 percent is very high."

The study was published in the August 4, ahead-of-print issue of the journal Science.

"When we find genes mutated in a majority of tumors, it is likely that the trajectory that regulated gene is of crucial importance for the development and the biology of the tumor," says Nickolas Papadopoulos, Ph.d., co-corresponding author, and Professor of Oncology at the Johns Hopkins Kimmel Cancer Center.

Finding of two additional new genes involved in oligodendrogliomas increases the opportunity for an effective combination drug therapy for tumor, Yan said. He foresees a combination cocktail of drugs similar to the treatments of the combination drug taken by HIV patients who would set up different routes that are involved in cancer and help in reducing the chance of relapsing, increasing chances of success.

The genes they identified are tumor suppressor genes. The cancer-related pathways relating to these genes can target for future treatments have become, said Yan.

"Tumor suppressor genes such as we found, CIC or FUBP1, will not be addressed directly by small molecules, because the mutated gene products result in loss of function, but the pathways that these genes are involved in could be targeted," said Yan.

"Another very important feature is that the genes as biomarkers can be used to this type of cancer to distinguish it from other types of brain tumors."

The researchers found CIC on chromosome 19 and FUBP1 on chromosome 1 on the basis of an initial study of seven oligodendrogliomas; they found two six mutations and mutations, respectively, in the seven tumors. Further study of 27 more of these tumors showed that there are respectively 12 and three mutations of CIC and FUBP1, were. The two were rarely mutated genes in other forms of cancer, which means they oligodendroglioma-specific genes.

These tumors also contained a glioma (brain tumor) gene mutation identified earlier by Yan and colleagues, the IDH mutations.

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Other authors included Darell Bigner and Roger McLendon of the Preston Robert Tisch Brain Tumor Center at Duke, the Pediatric Brain Tumor Foundation and the Department of Pathology at Duke, as well as co-corresponding authors Bert Vogelstein and Kenneth Kinzler of the Ludwig Center for cancer genetics and Howard Hughes medical institutions on Johns Hopkins Kimmel Cancer Center and lead author Chetan Bettegowda, chief resident in the Department of neurosurgery at Johns Hopkins in Baltimore. Other authors were from the Department of neurosurgery, Department of Otolaryngology-Head and neck surgery and the Department of pathology of the Johns Hopkins medical institutions; the Department of neurosurgery at the University of Texas MC Anderson Cancer Center and Baylor College of Medicine, and the Department of Neurology at the University of Sao Paulo in Brazil.

Funding away from the Virginia and D.K. Ludwig Fund for cancer research, the Pediatric Brain Tumor Foundation Institute, the Duke Comprehensive Cancer Center core, the Burroughs-Wellcome Fund, The James s. McDonnell Foundation, Fundacao de Amparo a Pesquisa do Estado de Sao Paulo, subsidies, the NCI Division of cancer prevention and NIH contracts and a NIH/NCI National Research Service Award. Under agreements between the Johns Hopkins University, Genzyme, exact sciences, Inostics, Qiagen, Invitrogen and personal genome Diagnostics, are some of the researchers from the Johns Hopkins right to a share of the royalties received by the University on the sale of products related to genes and technologies described in this manuscript.

Article reference:
Duke University Medical Center