August 5, 2011 — A study that provides a genetic map for oligodendroglioma, the second most common form of brain cancer, has identified 2 recurring genetic mutations that have not been previously associated with these tumors, according to researchers from Johns Hopkins University in Baltimore, Maryland, and Duke University in Durham, North Carolina.
The findings, published online August 4 in Science, might reveal the biologic cause of the tumors, suggest the authors, led by Chetan Bettegowda, MD, PhD, chief resident in the Department of Neurosurgery at Johns Hopkins.
Two thirds of 37 tumor samples had CIC and FUBP1 mutations, report the authors.
"Whenever we find genes mutated in a majority of tumors, it is likely that the pathway regulated by that gene is critical for the development and biology of the tumor," said coauthor Nickolas Papadopoulos, PhD, in a press statement. He is associate professor of oncology at the Johns Hopkins Kimmel Cancer Center.
"The study illustrates an important pathway that can be further studied for its therapeutic potential," noted coauthor Kenneth Kinzler, PhD, professor and codirector of the Ludwig Center at Johns Hopkins, when speaking with Medscape Medical News.
Another member of the research team explained how a therapy might work with these mutations.
The genes identified are tumor suppressor genes, said coauthor Hai Yan, MD, PhD, associate professor of pathology at Duke. "Tumor suppressor genes like the ones we found, CIC and FUBP1, won't be targeted 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," Dr. Yan explained.
The researchers initially analyzed 7 anaplastic oligodendrogliomas, which are a higher-grade form of the disease. In total, they sequenced the coding exons of 20,687 genes.
They identified 225 nonsynonymous somatic mutations, affecting 200 genes in the 7 tumors. There were an average of 32.1 nonsynonymous somatic mutations per tumor. This is similar to the number found in glioblastomas (35.6), the most common type of adult brain tumor.
There were a number of notable mutations identified, the authors say. On the strength of the findings in the initial 7 tumors, the investigators analyzed 27 more tumors for a select group of mutations, including those of CIC and FUBP1. Overall, 23 mutations of CIC or FUBP1 were identified in the 34 oligodendroglioma samples analyzed.
"Our identification of inactivating mutations of CIC or FUBP1 in a substantial fraction of oligodendrogliomas is likely to provide important insights into the pathogenesis of these tumors, as well as help refine their diagnosis, prognosis, and treatment options," they write.
CIC and FUBP1 genes are known to regulate cell-signaling processes, and CIC mutations have been linked — although rarely — to sarcoma and breast and prostate cancers, note the authors.
Human Genome Help
The CIC and FUBP1 mutations might be the "missing link" in what scientists describe as a "2-hit" theory of cancer development, according to the Johns Hopkins press statement.
In oligodendrogliomas, the first hit occurs in regions of chromosomes 1 and 19, which fuse together, resulting in a loss of genes on both chromosomes. Anywhere from 50% to 70% of oligodendroglioma patients have these DNA fusions, according to authors.
The second hit that allows oligodendrogliomas to develop might be mutations in the remaining copies of the CIC and FUBP1 genes on chromosomes 1 and 19 in these patients.
To date, the best biomarker for oligodendroglioma is the loss of heterozygosity of chromosomes 1p and 19q, note the authors.
In this study, the analysis of the 20,000-plus protein-coding genes in the human genome was greatly enabled by the Human Genome Project, said Dr. Kinzler.
"Thanks to the Human Genome Project and advances in cancer genome sequencing, a single study can now resolve decade-old questions and reveal the genetics of this brain cancer," he said. "Knowing the genetic roadmap of a cancer is the key to attacking it."
Dr. Kinzler explained that, before the completion of the Human Genome Project, scientists could only look at parts of the genome. He used the metaphor of fingerprinting at a crime scene to compare research before and after the project. In the past, he said, only a few suspects could be finger printed at any one time. With the human genome now detailed, researchers can finger print every possible suspect.
The study was funded by the Virginia and D.K. Ludwig Fund for Cancer Research, the Pediatric Brain Tumor Foundation, the Duke Comprehensive Cancer Center Core, the Burroughs Wellcome Fund, the James S. McDonnell Foundation, Fundação de Amparo à Pesquisa do Estado de São Paulo, the National Cancer Institute, and the National Institutes of Health. A number of the coauthors are entitled to a share of the royalties received by Johns Hopkins on the sale of products related to genes and technologies described in the study.
Science. Published online August 4, 2011. Abstract
The findings, published online August 4 in Science, might reveal the biologic cause of the tumors, suggest the authors, led by Chetan Bettegowda, MD, PhD, chief resident in the Department of Neurosurgery at Johns Hopkins.
Two thirds of 37 tumor samples had CIC and FUBP1 mutations, report the authors.
"Whenever we find genes mutated in a majority of tumors, it is likely that the pathway regulated by that gene is critical for the development and biology of the tumor," said coauthor Nickolas Papadopoulos, PhD, in a press statement. He is associate professor of oncology at the Johns Hopkins Kimmel Cancer Center.
"The study illustrates an important pathway that can be further studied for its therapeutic potential," noted coauthor Kenneth Kinzler, PhD, professor and codirector of the Ludwig Center at Johns Hopkins, when speaking with Medscape Medical News.
Another member of the research team explained how a therapy might work with these mutations.
The genes identified are tumor suppressor genes, said coauthor Hai Yan, MD, PhD, associate professor of pathology at Duke. "Tumor suppressor genes like the ones we found, CIC and FUBP1, won't be targeted 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," Dr. Yan explained.
The researchers initially analyzed 7 anaplastic oligodendrogliomas, which are a higher-grade form of the disease. In total, they sequenced the coding exons of 20,687 genes.
They identified 225 nonsynonymous somatic mutations, affecting 200 genes in the 7 tumors. There were an average of 32.1 nonsynonymous somatic mutations per tumor. This is similar to the number found in glioblastomas (35.6), the most common type of adult brain tumor.
There were a number of notable mutations identified, the authors say. On the strength of the findings in the initial 7 tumors, the investigators analyzed 27 more tumors for a select group of mutations, including those of CIC and FUBP1. Overall, 23 mutations of CIC or FUBP1 were identified in the 34 oligodendroglioma samples analyzed.
"Our identification of inactivating mutations of CIC or FUBP1 in a substantial fraction of oligodendrogliomas is likely to provide important insights into the pathogenesis of these tumors, as well as help refine their diagnosis, prognosis, and treatment options," they write.
CIC and FUBP1 genes are known to regulate cell-signaling processes, and CIC mutations have been linked — although rarely — to sarcoma and breast and prostate cancers, note the authors.
Human Genome Help
The CIC and FUBP1 mutations might be the "missing link" in what scientists describe as a "2-hit" theory of cancer development, according to the Johns Hopkins press statement.
In oligodendrogliomas, the first hit occurs in regions of chromosomes 1 and 19, which fuse together, resulting in a loss of genes on both chromosomes. Anywhere from 50% to 70% of oligodendroglioma patients have these DNA fusions, according to authors.
The second hit that allows oligodendrogliomas to develop might be mutations in the remaining copies of the CIC and FUBP1 genes on chromosomes 1 and 19 in these patients.
To date, the best biomarker for oligodendroglioma is the loss of heterozygosity of chromosomes 1p and 19q, note the authors.
In this study, the analysis of the 20,000-plus protein-coding genes in the human genome was greatly enabled by the Human Genome Project, said Dr. Kinzler.
"Thanks to the Human Genome Project and advances in cancer genome sequencing, a single study can now resolve decade-old questions and reveal the genetics of this brain cancer," he said. "Knowing the genetic roadmap of a cancer is the key to attacking it."
Dr. Kinzler explained that, before the completion of the Human Genome Project, scientists could only look at parts of the genome. He used the metaphor of fingerprinting at a crime scene to compare research before and after the project. In the past, he said, only a few suspects could be finger printed at any one time. With the human genome now detailed, researchers can finger print every possible suspect.
The study was funded by the Virginia and D.K. Ludwig Fund for Cancer Research, the Pediatric Brain Tumor Foundation, the Duke Comprehensive Cancer Center Core, the Burroughs Wellcome Fund, the James S. McDonnell Foundation, Fundação de Amparo à Pesquisa do Estado de São Paulo, the National Cancer Institute, and the National Institutes of Health. A number of the coauthors are entitled to a share of the royalties received by Johns Hopkins on the sale of products related to genes and technologies described in the study.
Science. Published online August 4, 2011. Abstract
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