Figure 20–23 The distinct types of DNA sequence changes found in oncogenes compared to tumor suppressor genes. In this diagram, mutations that change an amino acid are denoted by blue arrowheads, whereas mutations that truncate the polypeptide chain are marked by yellow arrowheads. (A) As in this example, oncogene mutations can be detected by the fact that the same nucleotide change is repeatedly found among the missense mutations in a gene. (B) For tumor suppressor genes, by contrast, missense mutations that abort protein synthesis by creating stop codons predominate. (Adapted from B. Vogelstein et al., Science 339:1546–1558, 2013.) chromosome alterations found in the particular primary tumor. As indicated, purple lines connect sites at which two different chromosomes have become joined to create an interchromosomal rearrangment, while green lines connect the sites of rearrangements found within a single chromosome. The intrachromosomal rearrangements can be seen to predominate, and most join neighboring sections of DNA that were originally located within 2 million nucleotide pairs of each other. The increases in copy number,
CANCER-CRITICAL GENES: hOW ThEY ARE FOUND AND WhAT ThEY DO
Cancer genome analysis reveals, first of all, the scale of gross genetic disruption in cancer cells. This varies greatly from one type of cancer and one cancer patient to another, both in severity and in character. In some cases, the karyotype—the set of chromosomes as they appear at mitosis—is normal or nearly so, but many point mutations are detected in individual genes, suggesting a failure of the repair mechanisms that normally correct local errors in the replication or maintenance of DNA sequences. Often, however, the karyotype is severely disordered, with many chromosome breaks and rearrangements. In some breast cancers, for example, genome sequencing reveals an astonishing scene of genetic chaos (Figure 20–24), with hundreds of chromosome breaks and translocations, resulting in many deletions, duplications, and amplifications of parts of the genome. In such cells, the normal machinery for avoidance or repair of DNA double-strand breaks is evidently somehow defective, destabilizing the genome by giving rise to broken chromosomes whose fragments then rejoin in random combinations. From the pattern of changes, one can infer that this disruptive process has occurred repeatedly during the evolution of the tumor, with a progressive increase of genetic disorder. Breast cancers showing the most extreme chromosome disorder are usually hard to treat and have a gloomy prognosis.
One survey of more than 3000 individual cancer specimens showed that on average 24 separate blocks of genetic material were duplicated in each tumor, amounting to 17% of the normal genome, and 18 blocks were deleted, amounting to 16% of the normal genome. Many of these changes were found repeatedly, suggesting that they contain cancer-critical genes whose loss (tumor suppressor genes) or gain (oncogenes) confers a selective advantage.
Whole-genome analysis also helps to explain some cancers that seem, at first sight, to be exceptions to the general rules. An example is retinoblastoma, with its early onset during childhood. If cancers in general require an accumulation of many genetic changes and are thus diseases of old age, what makes retinoblastoma different? Whole-genome sequencing confirms that in retinoblastoma, the tumor cells contain loss-of-function mutations in the Rb gene; but, astonishingly, they contain practically no mutations or genome rearrangements that affect any other oncogene or tumor suppressor gene. Instead, they contain many epigenetic modifications, which alter the level of expression of many known cancer-critical genes—as many as 15 in one well-analyzed case.
Many Mutations in Tumor Cells are Merely Passengers
Cancer cells generally contain many mutations in addition to gross chromosome abnormalities: point mutations can be scattered over the genome as a whole at a rate of about one per million nucleotide pairs, in addition to the abnormalities