Posted: February 1, 2011
TCGA Researchers Discover New Gene Changes and Signaling Pathways that Contribute to Glioblastoma Multiforme Development
Glioblastoma multiforme (GBM), the most common adult brain tumor, was the first of two cancer types to be studied in the pilot phase of The Cancer Genome Atlas (TCGA). In a 2008 Nature publication1, TCGA researchers reported on its comprehensive GBM analysis, an outcome of TCGA’s large-scale, multidimensional approach to cancer research. Examining the gene changes unique to 206 GBM tumors, TCGA scientists uncovered information about the role of certain genes in GBM tumor growth. They also gained new insight into the genes controlling important networks of molecular signals within tumor cells.
Gene Changes Implicated in GBM
The findings validated TCGA’s approach by confirming previously discovered GBM gene mutations and uncovering new mutations in these genes. For example, scientists have known that mutations in the NF1 gene are involved in GBM’s development, but they have been unsure how important a role they play. NF1 codes for the Neurofibromin 1 protein, which was first found to be mutated in neurofibromatosis, a genetic disease present at birth. Neurofibromatosis is defined by uncontrolled tissue growth, especially in the nervous system. The current paper demonstrates that NF1 mutations do indeed occur in GBM tumors. Forty-seven of the 206 tumors (23 percent) contained inactivating mutations in NF1. The NF1 gene, whose tumor-suppressor role becomes damaged in GBM, seems to be more relevant to GBM development than previously thought.
It was also previously known that the epidermal growth factor receptor (EGFR) gene acquires mutations in GBM. However, until the TCGA analysis, scientists did not know the extent to which EGFR mutations occurred. EGFR, found on the surface of some cells, is a protein to which epidermal growth factor binds and which affects cell growth and division. In the TCGA analysis, the EGFR gene was mutated in almost half of the GBM tumors examined. The researchers also discovered additional types of EGFR alterations that were not previously known. ERBB2 is a gene for a receptor that is closely related to EGFR. Previously, only one ERBB2 mutation had been found in one GBM tumor. TCGA scientists discovered several more ERBB2 mutations in the GBM tumors they analyzed. These discoveries of additional mutations in genes known to be involved in GBM solidified their importance in the disease and expanded the scope of scientists’ previous knowledge about them.
The study similarly verified the importance of the genes for another family of proteins called the PI(3)K complex. This group of proteins controls cell growth. The analysis confirmed the existence of already known mutations as well as new mutations, solidifying this group’s role in GBM tumor growth. The scientists also found mutations in other genes whose proteins interact with the PI(3)K complex. A network of interacting proteins forms a signaling pathway, which is how growth signals are passed along inside a cell. This contribution of more than one member of a signaling pathway to cancer development means that it is more informative for scientists to study mutations in the whole range of genes in a pathway, rather than a single gene. This information will help in the development of treatments that are tailored to the specific patterns of mutations in one or more pathways.
Pathways That May Be Important
Because they found multiple alterations in not just one, but many genes belonging to the same pathway of interacting proteins, the scientists’ next step was to determine which pathways were most important to GBM growth. They did this by examining 601 known mutations in the GBM tumors. They then placed them into groups according to the cell signaling pathway to which they belonged. Cell signaling is a process by which receptors on the cell’s surface catch chemical signals outside the cell and transmit them to the inside of the cell, setting off a flow of chemical reactions that promote cell growth. This approach revealed three major pathways to which most of the mutations belonged. These pathways are most crucial to GBM development. In 88 percent of the tumors, altered signaling occurred within the RTK/RAS/PI(3)K pathways. Altered signaling in the p53 pathway occurred in 87 percent of the tumors, while 78 percent showed altered signaling in the RB pathways. In 74 percent of the GBM tumors, gene changes existed in all three pathways, suggesting that abnormal signaling in all of the pathways is required for most GBM tumors to develop.
Gene Change Linked to Treatment Resistance
Finally, the TCGA researchers examined the MGMT gene, which codes for a protein that repairs damaged DNA. They found that it was methylated, or tagged with a chemical that can keep it from functioning, in 19 of 91 GBM tumors. The tumors with methylated MGMT were more likely to have damaging mutations in other repair genes, especially if these tumors were from patients treated with chemotherapy. Scientists and clinicians have known that patients with methylated MGMT are initially very responsive to chemotherapy treatment but can later develop resistance to the treatment. The study’s findings confirm that initial treatment of methylated MGMT tumors by chemotherapy can lead to the development of additional mutations in other DNA repair genes. This process results in highly mutated, treatment-resistant tumors. The authors speculate that patients with tumors having methylated MGMT can be treated with both chemotherapy and a drug that prevents repair gene mutations. They believe this approach may decrease the risk of resistance in these patients.
1The Cancer Genome Atlas Research Network. (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 455(7216):1061-1068. Download the PDF.