Mutaties bij twee bepaalde genen, CIC en FUBP1, zouden cruciale rol spelen in ontstaan van bepaalde vorm van een laaggradige hersentumor - oligodrendroglioom

9 augustus 2011: Bron: Science DOI: 10.1126/science.1210557

Wetenschappers hebben ontdekt dat mutaties (veranderingen) bij twee bepaalde genen, CIC en FUBP1, een cruciale rol lijken te spelen in het ontstaan van laaggradige hersentumoren in een bepaald gebied van de hersenen, zo geheten oligodrendroglioom. Wat dit betekent voor het eventueel behandelen van deze vorm van hersentumoren beschrijft Medscape in een artikel over deze studie. Hier een citaat uit dit artikel:

"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. Read more>>>>>

Hier het abstract van de genenstudie:

Mutations in CIC and FUBP1 contribute to human oligodendroglioma

+ Author Affiliations

¹Ludwig Center for Cancer Genetics and Howard Hughes Medical Institutions, Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21287, USA.
²Department of Neurosurgery, The Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA.
³Department of Otolaryngology-Head and Neck Surgery, The Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA.
⁴Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA.
⁵Department of Neurosurgery, The University of Texas MD Anderson Cancer Center and Baylor College of Medicine, Houston, TX 77030, USA.
⁶The Preston Robert Tisch Brain Tumor Center at Duke, The Pediatric Brain Tumor Foundation Institute and the Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA.
⁷Department of Neurology, School of Medicine, University of Sao Paulo, Sao Paulo, Brazil.

†To whom correspondence should be addressed. E-mail: vogelbe@jhmi.edu (B.V.); yan00002@mc.duke.edu (H.Y.); npapado1@jhmi.edu (N.P.); kinzlke@jhmi.edu (K.W.K.) ↵* These authors contributed equally to this work.

Abstract:

Oligodendrogliomas are the second most common malignant brain tumor in adults and exhibit characteristic losses of chromosomes 1p and 19q. To identify the molecular genetic basis for this alteration, we performed exomic sequencing of seven tumors. Among other changes, we found that the CIC gene (homolog of the Drosophila gene capicua) on chromosome 19q was somatically mutated in six cases and that the FUBP1 gene [encoding far upstream element (FUSE) binding protein] on chromosome 1p was somatically mutated in two tumors. Examination of 27 additional oligodendrogliomas revealed 12 and 3 more tumors with mutations of CIC and FUBP1, respectively, 58% of which were predicted to result in truncations of the encoded proteins. These results suggest a critical role for these genes in the biology and pathology of oligodendrocytes

hersentumoren, mutaties, FUBP1, CIC, genentest