The findings are reported in the Sept. 4, 2008, advance edition of Nature.

The TCGA team, comprised of more than 100 investigators from seven cancer centers and research institutions throughout the country, analyzed 601 genes in tumor samples from 91 glioblastoma multiforme (GBM) patients.

Investigators at the Johns Hopkins Kimmel Cancer Center and University of Southern California, members of the TCGA team, studied 2000 genes.

They reported findings on the MGMT gene, first linked to GBM in 1998 by Johns Hopkins investigators who found it was altered by a cellular process known as methylation. In 2002, they discovered that the gene alteration makes brain cancer cells more responsive to anticancer drugs known as alkylating agents.

While brain cancer patients with the MGMT alteration respond better to the commonly-used alkylating agent temozolomide, the new TCGA research found that treatment also appears to cause mutations in other genes, known as mismatch repair genes, essential to DNA repair. These mutations, they believe, lead to recurrence of the cancer, and these recurrent tumors contain unusually high numbers of gene mutations, making them resistant to treatment.

The investigators stress that treatment with temozolomide and radiation therapy is still the most effective therapy for glioblastoma patients.

"These current findings should help us devise new therapies that minimize the role MGMT plays in cancer recurrence," says Stephen Baylin, M.D., deputy director of the Johns Hopkins Kimmel Cancer Center and director of this portion of the TCGA study

Brain cancer affects more than 21,000 people in the United States each year. GBM is the most common and lethal form of brain cancer, with most patients surviving just 14 months from the time of diagnosis.

The TCGA is funded by the National Cancer Institute (NIH) and National Human Genome Research Institute. The program began in 2006 to accelerate understanding of the molecular basis of cancer through full-scale, systematic studies of the human gene changes involved in all types of cancer. GBM is the first cancer studied under the program. A report of the complete findings from the study can be found on the National Cancer Institute's Web site.

"This type of comprehensive, coordinated analysis of unprecedented multidimensional data is made possible by advanced technologies utilized by teams of scientists driven to solve complex questions," said NCI director John E. Niederhuber, M.D. in a NIH statement. "It will now fall to a dedicated cadre of laboratory scientists to turn this important information into new life-saving therapies and diagnostics for cancer."

The TCGA data is available to the research community through a database cancergenome.nih/dataportal.

Findings from a complementary but independent genomic study of GBM by Johns Hopkins Kimmel Cancer investigators are expected to be published in the Sept. 5, 2008, issue of Science Express.

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