Massive gene scan finds brain tumor clues

A sweeping survey of cancer genes has turned up previously unknown mutations that lead to brain cancer and possibly explain resistance to a common chemotherapy drug used to treat it, Boston researchers from a multi-center team report.

A paper appearing in Nature describes a systematic analysis of 206 glioblastoma multiforme tumors, the kind of cancer that Senator Edward M. Kennedy has. The gene search results come from the Cancer Genome Atlas Research Network, a $100 million pilot project funded by the National Institutes of Health to test this kind of large-scale systematic approach to cancer research.

The gene survey confirmed five mutations already identified in brain tumors and found three new ones. The researchers also tracked disruptions in cellular function that the mutations led to, including problems with cell division, cell growth, and repair of DNA damage.

One of the most exciting discoveries was a potential explanation for why patients who are successfully treated with the chemotherapy drug Temodar (temozolomide) develop resistance if their tumors come back, co-author Dr. Lynda Chin of Dana-Farber Cancer Institute and Harvard Medical School said in an interview. In those patients' tumors, a gene that was responsible for repairing DNA errors had developed hypermutations. These rapid genetic changes meant the drug was missing its mark.

This discovery makes the repair gene a potential target for a new drug that would avoid resistance to Temodar, Chin said. She and Dr. Matthew Meyerson of Dana-Farber and the Broad Institute of MIT and Harvard are the leading co-authors of the Nature paper, which is based on work by investigators at 18 institutions.

"The implication of that is, you might want to do a drug screen and design a drug that's particularly effective in a cell that does not have mismatch repair," she said. "I think the value of the genomic project approach is to discover these unanticipated relationships. If we even fast forward to personalized medicine, to get there we have to be able to understand all the changes in the genome and we have to be able to decipher what these changes mean."

The Nature paper appears on the same day that Science is publishing two reports from Johns Hopkins on the genomes of pancreatic cancer and brain cancer.