Coping with Complexity
Bert Vogelstein, M.D., Clayton professor of oncology and pathology at Johns Hopkins University, summarized the information collected to date from the first 100 cancer genomes that have been analyzed, 78 of which are published. Across various tumor types, the number of genetic alterations—primarily point mutations—typically ranges from 30 to 80. In pancreatic cancer, for example, the median number of altered genes is 44, with a range of 36 to 60.
For lung and melanoma tumors, the number of mutations increases to 100–200, which can be explained by the addition of a variety of alterations caused by carcinogens associated with tobacco and sun exposure. Leukemia and medulloblastoma, which develop more quickly, typically contain about 10 cancer-associated mutations.
The data indicates that mutations tend to accumulate as a tumor ages and evolves, and that most alterations are “passenger” mutations, rather than “driver” mutations, the latter of which are present in tumor suppressor genes or oncogenes and are directly responsible for driving oncogenic transformation. Differentiating driver from passenger mutations is a key challenge and the focus of much current research.
Of the 3,142 mutated (and potential) cancer genes found in these 100 genomes, about 286 are in tumor suppressor genes. This has important implications for drug discovery, noted Dr. Vogelstein, as “you can’t target something that is being suppressed.” Nearly all of the driver genes are part of 12 core signaling pathways.
Dr. Vogelstein described tumor heterogeneity as the “elephant in the room.” For example, two different people may have the same type of tumor with mutations affecting the same signaling pathway, but the mutations may be in different genes.
Most cancer genome studies to date have been done in model organisms, and Dr. Vogelstein emphasized the need to perform large-scale genome analysis studies in human cancer cells and the importance of developing an understanding of the pathways through which cancer genes operate in human cancer cells. This information will be essential for translating genomic information to drug discovery and for targeting pathways such as DNA repair pathways, angiogenesis pathways, and metabolic pathways—rather than individual mutant proteins.
Over the past 30 years, scientists have come to understand “most of the genes and all of the pathways in cancer,” said Dr. Vogelstein, and he does not expect any surprises such as the discovery of new cancer genes. “We know the landscape,” and it is sobering, he said, noting the complexity and challenges the cancer genome presents. Yet he is optimistic that “the mitigation of much disease caused by cancer is within our grasp.”