The pathway mapping promises to be particularly informative 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.

For example, a patient whose tumor has genetic alterations at one point in the CDK pathway might benefit from a drug that blocks CDK, while patients with mutations at another point in the same pathway might be predicted not to respond to such drugs. Similarly, while some drugs already used for GBM target the RTK pathway, the new findings suggest a need to tailor therapeutic cocktails to particular patterns of mutations in genes involved in that pathway.


The three pathways were interconnected and coordinately deregulated in most of the GBM tumors analyzed. Therefore, combination therapies directed against all three pathways may offer an effective strategy, the TCGA researchers state.

One particularly exciting finding with the potential for rapid clinical impact centers on the MGMT gene. Physicians already know patients with GBM tumors that have an inactivated, or methylated, MGMT gene respond better to temozolomide, an alkylating chemotherapy drug commonly used to treat GBM. By integrating methylation and sequencing data with clinical information about sample donors, TCGA's multi-dimensional analysis found that in patients with MGMT methylation, alkylating therapy may lead to mutations in genes that are essential for DNA repair, commonly known as mismatch repair genes. Such mutations then lead to the subsequent emergence of recurrent tumors that contain an unusually high number of DNA mutations, and that may be resistant to chemotherapy treatment. If follow-up studies confirm such a mechanism, researchers say first- or second-line treatments for such GBM patients may involve therapies designed to target the results of combined loss of MGMT and mismatch-repair deficiency. The new findings also may help clinical researchers figure out the best ways to combine alkylating chemotherapy drugs with the next generation of targeted therapeutics.

"This represents another major step towards our ultimate goal of using information about the human genome to improve human health,"said NHGRI Acting Director Alan E. Guttmacher, M.D. "It's thrilling to see what the cancer and genomics research communities can achieve through working together in a collaborative manner. I am confident that this paper is just the first of many exciting results that TCGA will generate."

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