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Cancer Genetics and Biology


The statement “cancer is a genetic disease” is true from 2 overlapping perspectives. First, analysis of the genome of a cancer cell almost always reveals specific acquired changes (point mutations, rearrangements, or amplifications) that play a fundamental role in transforming a normal cell into a cancer cell. As described in this chapter, knowledge of these changes has substantially improved our ability to treat and often cure childhood cancer. Second, in approximately 10% of childhood cancer patients, the child was born with a genetic change that substantially increased the risk of cancer developing. Identifying these at-risk children and families allows us to implement cancer surveillance at an early age in an attempt to identify the cancer at a stage that is more curable and where therapy may be less toxic. In some rare, particularly high-risk conditions, prophylactic surgery may be recommended to prevent cancer from developing.


The vast majority of cancer patients have acquired mutations in the genetic material (DNA) of their cancer cells. These somatic mutations associated with cancer differ from germline mutations in that they have been acquired by somatic cells, are not found in the normal tissues of the individual, and therefore cannot be transmitted to offspring. As a first approximation, these mutations can be placed into 2 large classes: gross chromosomal rearrangements (GCRs) and submicroscopic mutations. GCRs, also referred to as structural variations, can be recognized on a chromosomal metaphase spread, using a light microscope. They can lead to chromosomal deletions, amplifications, inversions, and translocations, resulting in production of oncogenic fusion genes, overexpression of proto-oncogenes, or silencing of tumor suppressor genes (TSGs).

Consequences of Gross Chromosomal Rearrangements: General Themes

The study of GCRs associated with childhood cancer has revealed several common themes. First, specific translocations (pairing of 2 different chromosome fragments) are associated with specific classes of cancer; for instance, the t(1;19)(q23;p13) translocation is found only in patients with pre–B-cell acute lymphoblastic leukemia (ALL) and no other forms of childhood leukemia. Although there are exceptions to this generalization, the association of specific translocations with specific types of cancer supports the contention that these recurrent GCRs are biologically selected causal events leading to malignant transformation. A second theme is that recurrent GCRs typically lead to either production of an oncogenic fusion gene derived from portions of 2 different genes found on each of the chromosomes making up the translocation, such as the EWS-FLI1 fusion gene associated with Ewing sarcoma; or alternatively, the translocation can lead to dysregulated expression of an intact gene, caused by fusion of promoter/enhancer elements of a second gene, such as activation of the MYC gene by fusion to IGH regulatory elements in Burkitt lymphoma. A third theme is that genes affected by GCRs often encode either transcription factors (so-called “master-regulatory” genes), or tyrosine kinase genes involved in signal ...

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