The first results of a large scale, comprehensive study of the most common form of brain cancer, glioblastoma (GBM), have been reported by The Cancer Genome Atlas (TCGA) Research Network.   The collaborative effort was funded by the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI) of the National Institutes of Health (NIH).   

In a paper published this week in the advanced online edition of the journal Nature, the TCGA team describes the discovery of new genetic mutations and other types of DNA alterations with potential implications for the diagnosis and treatment of GBM.

Among the TCGA findings are the identification of many gene mutations involved in GBM, including three previously unrecognized mutations that occur with significant frequency; and the delineation of core pathways disrupted in this type of brain cancer.  An unexpected observation also emerged that points to a potential mechanism of resistance to a common chemotherapy drug used for brain cancer.

More than 21,000 new cases of brain cancer are predicted in the United States this year, with more than 13,000 people likely to die from the disease.  GBM, which is the type of brain cancer most often found in adults, is a very fast-growing type of tumor.  Most patients with GBM die of the disease within approximately 14 months of diagnosis.


Sequencing-1

Source: Nature News


The TCGA network analyzed the complete sets of DNA, or genomes, of tumor samples donated by 206 patients with GBM. The work complements and expands upon a parallel study by Johns Hopkins researchers of 22 GBM tumors, which was also published today in the journal Science.

Like most cancers, GBM arises from changes that accumulate in cells' DNA over the course of a person's life, changes that may eventually lead to the cells' uncontrolled growth.  However, until recently, scientists have understood little about the precise nature of these DNA changes and their impact on key biological pathways that are important to the development of new interventions.

The NCI and the NHGRI initiated TCGA in 2006 to accelerate understanding of the molecular basis of cancer through the application of current genome characterization technologies, including large-scale genome sequencing. TCGA was launched as a pilot program to determine the feasibility of a full-scale effort to potentially systematically explore the universe of genomic changes involved in all types of human cancer.

In the Nature paper, the TCGA Research Network describes the interim results of its analyses of GBM, the first type of cancer to be studied in the TCGA pilot.  This pioneering work pulled together and integrated multiple types of data generated by several genome characterization technologies from investigators at 18 different participating institutions and organizations.  

The data include small changes in DNA sequence, known as genetic mutations; larger-scale changes in chromosomes, known as copy number variations and chromosomal translocations; the levels of protein-coding RNA being produced by genes, known as gene expression; patterns of how certain molecules, such as methyl groups, interact with DNA, known as epigenomics; and information related to patients' clinical treatment.

TCGA researchers sequenced 601 genes in GBM samples and matched control tissue, uncovering three significant genetic mutations not previously reported to be common in GBM.  The affected genes were:

– NF1, a gene previously identified as the cause of neurofibromatosis 1, a rare, inherited disorder characterized by uncontrolled tissue growth along nerves

– ERBB2, a gene that is well-known for its involvement in breast cancer

– PIK3R1, a gene that influences activity of an enzyme called PI3 kinase that is deregulated in many cancers.  PI3 kinase already is a major target for therapeutic development. The discovery of frequent mutations in the PIK3R1 gene means that GBM patients' responses to PI3 kinase inhibitors may be dictated by whether or not their tumors have mutated versions of the gene.

The TCGA team combined sequencing data with other types of genome characterization information, such as gene expression and DNA methylation patterns, to generate an overview that delineated core biological pathways potentially involved in GBM.  

The three pathways, each of which was found to be disrupted in more than three-quarters of GBM tumors, were:

– CDK/cyclin/CDK inhibitor/RB pathway, which is involved in the regulation of cell division
– p53 pathway, which is involved in response to DNA damage and cell death
– RTK/RAS/PI3K pathway, which is involved in the regulation of growth factor signals.

The pathway mapping may provide information for researchers working to develop therapeutic strategies that are aimed more precisely at specific cancers or that are better tailored to each patient's particular subtype of tumor, however, functional studies were not included in the analysis.  These studies investigate how the mutations aid tumor development and what drugs might target the pathways essential to tumor survival.

Overall, the CGA study and other recent trials have found that individual cancer patients each carry dozens of genetic mutations, an average of 63 alterations in pancreatic cancer and 47 DNA mutations glioblastoma, for example.  Similar results have been found in previous studies of other cancers. 

This means that it unlikely that the cancers will be cured by drugs that target just one or a few genes, so a multi-factorial approach is most likely going to be the best way forward looking at different combinations of oncology drugs that target different pathways.

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