Nature paper describes how alkylating chemotherapy given to patients with a methylated MGMT gene may lead to recurrent tumors.

The Cancer Genome Atlas (TCGA) research network reports that they have discovered a potential mechanism of resistance to a chemotherapy drug used for glioblastoma multiforme (GBM). Interim analysis of their sequencing efforts also revealed three new gene mutations linked to GBM and validated a number of previously identified genes. Additionally, the investigators found three signaling pathways that were disrupted in this type of cancer.

It is already known that patients with GBM tumors who have a methylated MGMT gene respond better to temozolomide, an alkylating chemotherapy drug. TCGA’s analysis found, however, 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, the scientists note that first- or second-line treatments for such GBM patients should involve therapies designed to target the results of combined loss of MGMT and mismatch-repair deficiency.

Another major finding was mutations in three new genes: the NF1 gene, which causes neurofibromatosis, the ERBB2 gene, known to be involved in breast cancer, and PIK3R1, a gene that influences activity of an enzyme called PI3 kinase, which is deregulated in many cancers.

The investigators also established that the three signaling pathways they identified were disrupted in more than three-quarters of the GBM tumors. Since they are all interconnected and were seen to be coordinately deregulated in most of the GBM tumors analyzed, the team suggests that combination therapies directed against all three pathways may offer an effective strategy.

The following are the pathways identified in the TCGA study: the cyclin-dependent kinase/retinoblastoma pathway, which regulates cell division; the p53 tumor suppressor pathway, which is involved in response to DNA damage and cell death; and the receptor tyrosine kinase pathway, which carries signals that control cell growth.

The TCGA network analyzed the genomes of tumor samples donated by 206 patients with GBM. They sequenced 601 genes in GBM samples and matched control tissue.

TCGA data is being made available to the research community through an online database.  

About 20 institutes collaborated on this research, which was headed by Dana-Farber Cancer Institute and The Broad Institute of MIT and Harvard. The study was published on September 4 in Nature.


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