Role of Genes in Pediatric Cancer
Cancers are genetic diseases, triggered by harmful changes, or mutations, in the DNA of normal cells. The human genetic instruction book is written in the four-letter alphabet of the DNA molecule—A, T, C, and G. Cells can accumulate misspellings, or mutations, in that instruction book. These mutations remove regulatory controls, allowing cells to multiply and spread unchecked. Every cancer arises from a series of mutations, each of which alters a normal biological process in the cell and leads to the transformation of a normal cell to a malignant cell.
These mutations occur among the 3 billion DNA base pairs of the human genome; and until now scientists have been unable to identify the great majority of such mutations because technology has limited their ability to quickly assess the entire genome. Only 350 of an estimated 2,000 cancer genes have been found and as a result, the genetic causes of most cancers remain elusive.
Many geneticists suspect it typically takes a relatively small number, perhaps as few as eight to 12 mutations in key genes, to cause cancer. Given the rate at which mutations occur in the cells of the body, it would seem to be a mathematical impossibility for a child to get cancer, and it’s the reason most adults don’t get cancer until late in life. The fact that children develop tumors suggests that different mechanisms are at work in the development of pediatric cancer. If scientists can pinpoint the critical mutations that drive these tumors, they can develop diagnostic and prognostic tests and identify targets for new, more effective treatments.
We have seen examples of what a better understanding of genomics can do in the fight against childhood cancer. Research conducted by St. Jude Children’s Research Hospital scientists has increased understanding about the genetic lesions that drive pediatric acute lymphoblastic leukemia, the most common form of pediatric cancer. In groundbreaking work published during the last two years, scientists identified mutations in specific genes in the leukemia cells that alter the normal ability of the cells to mature and proliferate. The presence of a subset of these newly identified genetic alterations now allows doctors to identify patients for whom current therapies are unlikely to be effective and who may benefit from more aggressive experimental approaches. Moreover, one of the identified genetic alterations is an ideal target for new drugs that block the activity of the mutant product.
Investigators at St. Jude and Washington University are embarking on an unprecedented effort to search the vast landscape of the human genome for the mutations that drive the malignancies of childhood cancers. The three-year project is the largest whole-genome sequencing of pediatric cancers ever conducted, and seeks to create the foundation of knowledge that will deliver the next decades’ childhood cancer treatments.
