As we have seen, activating mutations in growth-promoting and anti-apoptotic genes and loss-of-function mutations in growth-inhibiting and cell death genes bring about oncogenic transformation. Identifying these mutations and understanding how the affected genes function is providing key insights into the process of tumorigenesis and paving the way for the development of new therapies. It is thus not surprising that researchers have long been hunting for oncogenes and tumor-suppressor genes.

In the 1960s, researchers first realized that some cancers harbor characteristic chromosome alterations. Chronic myelogenous leukemia (CML), a common leukemia in humans, was found to be associated with the Philadelphia chromosome (Figure 24-19a), which is generated by a translocation between chromosomes 22 and 9. The two chromosomes exchange their terminal regions, which leads to a characteristic alteration in the size of chromosome 22 that can be detected by light microscopy. At the breakpoint of this translocation, a new fusion protein, the BCR-ABL fusion, is generated, creating a protein kinase that phosphorylates proteins that the wild-type ABL kinase normally does not phosphorylate, thereby activating many intracellular signal-transducing proteins. If this translocation occurs in a hematopoietic cell in the bone marrow, the activity of the chimeric BCR-ABL oncogene results in the initial phase of CML, characterized by an expansion in the number of white blood cells. A second loss-of-function mutation in a cell carrying the BCR-ABL fusion (e.g., in the tumor-suppressor genes p53 or RB) leads to acute leukemia, which is often fatal.

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The CML chromosomal translocation was only the first of a long series of distinctive, or “signature,” chromosomal translocations linked to particular forms of leukemia. Many of these translocations involve genes encoding transcriptional regulators, particularly transcriptional regulators of Hox genes, a group of transcription factors required for cell proliferation and differentiation during embryonic development. Each link that is found presents an opportunity for greater understanding of the disease, earlier diagnosis, and new therapies. In the case of CML, as we will see shortly, that second step to successful therapy has already been taken.

The development of DNA sequencing technologies has revolutionized the hunt for cancer genes. Combining high-throughput sequencing methods with methods that specifically allow for the capture of the genomic DNA that contains known protein-coding sequences has facilitated the systematic analysis of human tumors. To date we have sequence information on virtually all human tumor types. Furthermore, the gathering of sequence information from many tumors of a specific type is beginning to generate comprehensive lists of mutations, amplifications, deletions, and translocations that are characteristic of specific tumor types. The picture that emerges shows that only a few cancer genes are mutated in a high proportion of any specific cancer type. Most are mutated in only 2–10 percent of tumors of a particular type. This pattern makes the identification of cancer “driver mutations” among many cancer “passenger mutations” challenging, but with an ever-increasing number of tumor sequences and the development of statistical tools, scientists hope to be able to create comprehensive catalogues of true cancer genes and to assign degrees to which individual cancer genes contribute to the disease in the not too distant future.

Cancer genome sequencing also showed that different tumor types have dramatically different levels of genetic changes, with some cancer types harboring relatively few genetic changes and others exhibiting highly complex mutational patterns. It also appears that certain tumor types are associated with characteristic mutational patterns. For example, it was the cancer genome sequencing effort that discovered chromothripsis, the shattering and random stitching together of individual chromosomes, as a characteristic of aggressive neuroblastomas. Sequencing of tumor genomes not only holds great promise in identifying new cancer genes, but as we will see next, is also becoming an integral tool of disease treatment.