School of Medicine scientists, working as part of a large-scale federally funded research collaboration, have discovered new genetic mutations and molecular pathways underlying glioblastoma, the most common form of brain cancer and the most aggressive.
The first results of this comprehensive genetic study were published Sept. 4 in the advance online edition of Nature. The findings lay the foundation for developing new ways to diagnose and treat the deadly disease.
“This is extremely exciting,” said Richard K. Wilson, Ph.D., director of the Genome Sequencing Center. “This is exactly why we sequenced the human genome — so that we would have a reference point for looking at individual human genomes from people who have a disease like cancer to try to understand what’s gone wrong. Only then can we start to think about how to use that information to better diagnose their disease, delineate their cancer subtype and identify more targeted therapies.”
The researchers identified numerous genetic mutations involved in glioblastoma, including three previously unrecognized mutations that occur frequently, and defined core molecular pathways that are disrupted. Among the most exciting results is an unexpected observation 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. Most patients with glioblastoma die of the disease within 14 months of diagnosis.
The scientists, all part of The Cancer Genome Atlas (TCGA) Research Network, analyzed the complete sets of DNA, or genomes, of tumor samples donated by 206 patients with glioblastoma. The work complements and expands upon a parallel study by Johns Hopkins researchers of 22 glioblastoma tumors, which was published Sept. 4 in Science.
School of Medicine scientists brought their experience to the project by formulating the sequencing strategy, contributing tumor sequence data and developing the computer software and tools to analyze the resulting genetic data.
Wilson likened finding the genetic changes involved in glioblastoma to looking for a needle in a haystack.
“All humans have considerable DNA variations at the level of the genome, and that is completely normal,” Wilson said. “We had to find the few DNA base changes — the needles — linked to glioblastoma in a haystack of 6 billion bases of DNA that make up the full complement of genetic material in humans.”
Like most cancers, glioblastoma 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.
In the Nature paper, the TCGA Research Network describes the interim results of its analyses of glioblastoma, the first type of cancer to be studied as part of the research collaboration. The pioneering work integrated data, including 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.
The TCGA team combined sequencing data with other types of genome characterization information to generate an unprecedented overview that dilineated three core biological pathways potentially involved in glioblastoma. The pathway mapping promises to be informative for researchers developing therapeutic strategies aimed at specific cancers or that are better tailored to each patient’s particular subtype of tumor.