Over the past decade, comprehensive sequencing efforts have revealed the genomic landscapes of common forms of human cancer. In this review, Vogelstein at el. summarize what has been learned about cancer genomes from these sequencing studies and what this information has taught us about cancer biology and future cancer management strategies.
Some key points of interest for future research include:
- Consistent genetic alterations that distinguish cancers that metastasize from cancers that have not yet metastasized remain to be identified. This may be the result of technological limitations, lack of sufficiently detailed research, or simply the stochastic nature of metastasis.
- Originally, driver genes referred to genes which harbored driver mutations that caused a selective growth advantage. However, driver genes may also include that are overexpressed, underexpressed, or epigenetically altered in tumors, or those that enhance or inhibit some aspect of tumorigenicity when their expression is experimentally manipulated, and yet contain no driver mutations. To reconcile the two connotations of driver genes, Vogelstein et al. suggest that genes suspected of increasing the selective growth advantage of tumor cells be categorized as either “Mut-driver genes” or “Epi-driver genes.”
- As for how many more Mut-driver genes are yet to be discovered, Vogelstein et al. believe that a plateau is being reached, because the same Mut-driver genes keep being “rediscovered” in different tumor types. More Mut-driver genes will undoubtedly be discovered, but these will likely be in uncommon tumor types that have not yet been studied in depth.
- Although classic epidemiologic studies have suggested that solid tumors ordinarily require five to eight alterations in driver genes in order to develop, the actual number of driver gene mutations observed in tumors is often much lower, particularly in pediatric tumors. These “missing mutations” may be explained be technical issues such as imperfections in genome-wide sequencing. Another potential explanation is in Epi-driver genes. Given that Epi-driver genes are likely to compose a major component of unidentified mutations, further research on this topic is essential.
- Heterogeneity exists among the cells of one tumor, among different metastatic lesions of the same patient, among cells of an individual metastasis, and among the tumors of different patients. Understanding these different types of heterogeneity is important for efforts to individualize treatment.
- The recognition that certain tumors contain activating mutations in driver genes encoding protein kinases has already led to the development of small-molecule inhibitor drugs targeting those kinases. Vogelstein et al. believe that greater knowledge of these
pathways and the ways in which they function is the most pressing need in basic cancer research. Successful research on this topic should allow the development of agents that target, albeit indirectly, defective tumor suppressor genes.